US10401364B2 - Drug selection for colorectal cancer therapy using receptor tyrosine kinase profiling - Google Patents
Drug selection for colorectal cancer therapy using receptor tyrosine kinase profiling Download PDFInfo
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- US10401364B2 US10401364B2 US15/636,534 US201715636534A US10401364B2 US 10401364 B2 US10401364 B2 US 10401364B2 US 201715636534 A US201715636534 A US 201715636534A US 10401364 B2 US10401364 B2 US 10401364B2
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- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57419—Specifically defined cancers of colon
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/71—Assays involving receptors, cell surface antigens or cell surface determinants for growth factors; for growth regulators
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/91—Transferases (2.)
- G01N2333/912—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
- G01N2333/91205—Phosphotransferases in general
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Definitions
- the process of signal transduction in cells is responsible for a variety of biological functions including, but not limited to, cell division and death, metabolism, immune cell activation, neurotransmission, and sensory perception to name but a few. Accordingly, derangements in normal signal transduction in cells can lead to a number of disease states such as diabetes, heart disease, autoimmunity, and cancer.
- EGF epidermal growth factor
- EGFR epidermal growth factor receptor
- the phosphorylated tyrosine residues on the activated EGFR provide a docking site for the binding of SH2 domain containing adaptor proteins such as GRB2.
- GRB2 In its function as an adaptor, GRB2 further binds to a guanine nucleotide exchange factor, SOS, by way of an SH3 domain on GRB2.
- SOS guanine nucleotide exchange factor
- the formation of the complex of EGFR-GRB2-SOS leads to SOS activation to a guanine nucleotide exchange factor that promotes the removal of GDP from Ras. Upon removal of GDP, Ras binds GTP and becomes activated.
- Ras binds to and activates the protein kinase activity of RAF kinase, a serine/threonine-specific protein kinase.
- RAF kinase a protein kinase cascade that leads to cell proliferation.
- RAF kinase then phosphorylates and activates MEK, another serine/threonine kinase.
- MEK mitogen-activated protein kinase
- MAPK mitogen-activated protein kinase
- MAPK mitogen-activated protein kinase
- MAPK mitogen-activated protein kinase
- the phosphorylation of RSK by MAPK results in activation of RSK, which in turn phosphorylates ribosomal protein S6.
- Another known target of MAPK is the proto-oncogene, c-Myc, a gene important for cell proliferation, which is mutated in a variety of cancers.
- MAPK also phosphorylates and activates another protein kinase, MNK, which in turn phosphorylates the transcription factor, CREB.
- MNK protein kinase
- MAPK also regulates the transcription of the Fos gene, which encodes yet another transcription factor involved in cell proliferation. By altering the levels and activities of such transcription factors, MAPK transduces the original extracellular signal from EGF into altered transcription of genes that are important for cell cycle progression.
- Cetuximab is an example of a monoclonal antibody inhibitor, which binds to the extracellular ligand binding domain of EGFR, thus preventing the binding of ligands which activate the EGFR tyrosine kinase.
- gefitinib and erlotinib are small molecules which inhibit the intracellularly-located EGFR tyrosine kinase.
- EGFR is unable to undergo autophosphorylation at tyrosine residues, which is a prerequisite for binding of downstream adaptor proteins, such as GRB2.
- the present invention provides a method for evaluating the effectiveness of potential anticancer therapies for an individual patient with colorectal cancer. As such, the present invention provides methods for assisting a physician in selecting a suitable cancer therapy for the treatment of colorectal cancer at the right dose and at the right time for every patient.
- the present invention provides compositions and methods for detecting the status (e.g., expression and/or activation levels) of components of signal transduction pathways in tumor cells from a colorectal cancer.
- Information on the expression and/or activation states of components of signal transduction pathways e.g., HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, SHC, and other pathway proteins
- HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, SHC, and other pathway proteins can be used for colorectal cancer diagnosis, prognosis, and in the design of cancer treatments for colorectal cancer.
- the present invention provides methods for therapy selection by detecting, quantifying, and comparing the expression levels and/or activation levels of a plurality of dysregulated signal transduction molecules in colorectal tumor tissue in a specific, multiplex, high-throughput assay, such as a Collaborative Enzyme Enhanced Reactive Immunoassay (CEERTM).
- CEERTM Collaborative Enzyme Enhanced Reactive Immunoassay
- the present invention also provides methods for the selection of appropriate therapy (e.g., single drugs or combinations of drugs) to down-regulate or shut down a dysregulated signaling pathway implicated in colorectal cancer.
- the present invention comprises signal transduction pathway profiling in combination with detecting (e.g., genotyping for) the presence (or absence) of one or more somatic mutations (e.g., detecting the presence or absence of one, two, three, four, or more mutations resident within the KRAS, BRAF, and/or PIK3CA oncogenes) in tumor tissues or other samples obtained from colorectal cancer patients.
- detecting e.g., genotyping for
- somatic mutations e.g., detecting the presence or absence of one, two, three, four, or more mutations resident within the KRAS, BRAF, and/or PIK3CA oncogenes
- the present invention can advantageously be used to facilitate the design of personalized therapies for patients with colorectal cancer.
- CEERTM Collaborative Enzyme Enhanced Reactive Immunoassay
- the present invention is based, in part, upon the surprising discovery that signal transduction pathway profiling of colorectal cancer cells using a specific, multiplex, high-throughput assay such as CEERTM can advantageously provide critical information for selecting the most effective targeted agents (e.g., for single, combination, or sequential therapy) for the treatment of colorectal cancer.
- Example 1 provides an exemplary comprehensive profiling of colorectal cancer patients via multiplexed functional pathway signature and somatic mutation analysis.
- Example 2 provides an exemplary comprehensive molecular analysis of oncogenic mutation and signaling pathway profile markers in primary and metastatic colorectal cancers.
- the present invention is also based, in part, upon the surprising discovery that higher levels of expression and/or activation of non-ErbB receptor tyrosine kinases (RTKs) such as cMET and/or IGF1R were observed in KRAS mutant colorectal cancer patients when compared to KRAS wild-type colorectal cancer patients. See, Example 4 below.
- RTKs non-ErbB receptor tyrosine kinases
- the present invention provides methods for the rational selection of a combination of targeted agents based upon a combination of signal transduction pathway profiling and somatic mutation analysis.
- the present invention enables the identification of KRAS mutant patients with both ErbB-driven and ErbB-independent RTK expression and/or activation who would benefit from combination therapy and the selection of appropriate therapies targeting ErbB RTKs (e.g., HER1, HER2, HER3, and/or HER4) and non-ErbB RTKs (e.g., cMET and/or IGF1R).
- ErbB RTKs e.g., HER1, HER2, HER3, and/or HER4
- non-ErbB RTKs e.g., cMET and/or IGF1R
- the methods of the present invention provide accurate prediction, selection, and monitoring of patients with colorectal cancer most likely to benefit from targeted therapy by performing pathway profiling using multiplexed, antibody-based proximity assays, alone or in combination with somatic mutation analysis, and comparing the pathway profile and/or somatic mutation analysis to prognostic molecular profiles predictive of a patient's response to particular anticancer therapies.
- FIG. 1 shows the KRAS and BRAF mutations that were identified in tumor samples obtained from colorectal cancer patients as described in Example 1.
- FIG. 2 shows the expression and/or activation levels of components of signal transduction pathways including HER1, cMET, HER2, HER3, IGF-1R, cKIT, PI3K, AKT, ERK, and SHC in tumor samples obtained from colorectal cancer patients as described in Example 1.
- FIG. 3 shows that the expression levels of cMET and IGF1R were significantly higher in KRAS mutant CRC patients than in KRAS WT CRC patients.
- FIG. 4 shows that the activation (i.e., phosphorylation) level of cMET was significantly higher in KRAS mutant CRC patients than in KRAS WT CRC patients.
- the present invention provides methods for detecting the status (e.g., expression and/or activation levels) of one or a plurality of components of signal transduction pathways in tumor cells derived from colorectal tumor tissue or circulating cells of a colorectal tumor with an assay such as a specific, multiplex, high-throughput proximity assay as described herein (e.g., Collaborative Enzyme Enhanced Reactive Immunoassay (CEERTM)).
- CEERTM Collaborative Enzyme Enhanced Reactive Immunoassay
- the present invention comprises signal transduction pathway profiling in combination with genotyping for the presence or absence of one or more somatic mutations in genes such as KRAS, BRAF, and/or PIK3CA (e.g., at one, two, three, four, five, or more polymorphic sites such as a single nucleotide polymorphism (SNP) in one or more of these genes) in tumor tissues or other samples obtained from colorectal cancer patients.
- genes such as KRAS, BRAF, and/or PIK3CA (e.g., at one, two, three, four, five, or more polymorphic sites such as a single nucleotide polymorphism (SNP) in one or more of these genes) in tumor tissues or other samples obtained from colorectal cancer patients.
- SNP single nucleotide polymorphism
- the signal transduction pathway profiling of the invention comprises determining the expression level (e.g., total amount) of at least one or more of HER1, HER2, HER3, cMET, cKIT, IGF-1R, and/or CK (i.e., cytokeratin) and/or determining the activation level (e.g., level of phosphorylation (“p”) or complex formation) of at least one or more of HER1 (e.g., pHER1), HER2 (e.g., pHER2), HER3 (e.g., pHER3), cMET (e.g., pcMET), cKIT (e.g., pcKIT), IGF-1R (e.g., pIGF-1R), PI3K (e.g., PI3K complex), AKT (e.g., pAKT), ERK (e.g., pERK), and/or SHC (e.g.
- HER1
- the present invention also provides methods for the rational selection of anticancer drug therapy tailored to target one or more specific signal transduction pathway components (e.g., non-ErbB receptor tyrosine kinases (RTKs) and/or ErbB RTKs) with higher levels of expression and/or activation detected in a cancer cell obtained from a patient with a somatic mutation in an oncogene.
- RTKs non-ErbB receptor tyrosine kinases
- ErbB RTKs ErbB receptor tyrosine kinases
- the methods of the present invention rely on the detection or measurement of higher levels of expression and/or activation of non-ErbB RTKs such as cMET and/or IGF1R in KRAS mutant patients compared to KRAS wild-type patients.
- the present invention enables the identification of KRAS mutant patients with both ErbB-driven and ErbB-independent RTK expression and/or activation who would benefit from combination therapy and the selection of appropriate therapies targeting ErbB RTKs (e.g., HER1, HER2, HER3, and/or HER4) and non-ErbB RTKs (e.g., cMET and/or IGF1R).
- ErbB RTKs e.g., HER1, HER2, HER3, and/or HER4
- non-ErbB RTKs e.g., cMET and/or IGF1R
- the present invention also provides methods for selecting appropriate therapies to downregulate one or more deregulated signal transduction pathways involved in colorectal cancer. Therefore, the present invention may be used to facilitate the design of personalized therapies based on the particular molecular signature provided by the collection of total and/or activated signal transduction proteins, alone or in combination with somatic mutation analysis, in a given patient's colorectal tumor.
- cancer is intended to include any member of a class of diseases characterized by the uncontrolled growth of aberrant cells.
- the term includes all known cancers and neoplastic conditions, whether characterized as malignant, benign, soft tissue, or solid, and cancers of all stages and grades including pre- and post-metastatic cancers.
- Examples of different types of cancer include, but are not limited to, digestive and gastrointestinal cancers such as colorectal cancer, gastric cancer (e.g., stomach cancer), gastrointestinal stromal tumors (GIST), gastrointestinal carcinoid tumors, colon cancer, rectal cancer, anal cancer, bile duct cancer, small intestine cancer, and esophageal cancer; breast cancer; lung cancer (e.g., non-small cell lung cancer (NSCLC)); gallbladder cancer; liver cancer; pancreatic cancer; appendix cancer; prostate cancer, ovarian cancer; renal cancer (e.g., renal cell carcinoma); cancer of the central nervous system; skin cancer; lymphomas; gliomas; choriocarcinomas; head and neck cancers; osteogenic sarcomas; and blood cancers.
- a “tumor” comprises one or more cancerous cells.
- analyte includes any molecule of interest, typically a macromolecule such as a polypeptide, whose presence, amount (expression level), activation state, and/or identity is determined.
- signal transduction molecule or “signal transducer” includes proteins and other molecules that carry out the process by which a cell converts an extracellular signal or stimulus into a response, typically involving ordered sequences of biochemical reactions inside the cell.
- signal transduction molecules include, but are not limited to, receptor tyrosine kinases such as EGFR (e.g., EGFR/HER1/ErbB1, HER2/Neu/ErbB2, HER3/ErbB3, HER4/ErbB4), VEGFR1/FLT1, VEGFR2/FLK1/KDR, VEGFR3/FLT4, FLT3/FLK2, PDGFR (e.g., PDGFRA, PDGFRB), c-KIT/SCFR, INSR (insulin receptor), IGF-IR, IGF-IIR, IRR (insulin receptor-related receptor), CSF-1R, FGFR 1-4, HGFR 1-2, CCK4, TRK A-C, c-MET, RON, EPHA 1-8,
- activation state refers to whether a particular signal transduction molecule is activated.
- activation level refers to what extent a particular signal transduction molecule is activated.
- the activation state typically corresponds to the phosphorylation, ubiquitination, and/or complexation status of one or more signal transduction molecules.
- Non-limiting examples of activation states include: HER1/EGFR (EGFRvIII, phosphorylated (p-) EGFR, EGFR: Shc, ubiquitinated (u-) EGFR, p-EGFRvIII); ErbB2 (p-ErbB2, p95HER2 (truncated ErbB2), p-p95HER2, ErbB2: Shc, ErbB2: PI3K, ErbB2: EGFR, ErbB2: ErbB3, ErbB2: ErbB4); ErbB3 (p-ErbB3, truncated ErbB3, ErbB3: PI3K, p-ErbB3: PI3K, ErbB3: Shc); ErbB4 (p-ErbB4, ErbB4: Shc); c-MET (p-c-MET, truncated c-MET, c-Met:HGF complex); AKT1 (p-AKT
- oncogene includes a gene that has the potential to cause cancer.
- oncogenes include growth factors or mitogens such as c-Sis; receptor tyrosine kinases such as EGFR, HER2, PDGFR, and VEGFR; cytoplasmic tyrosine kinases such as Abl and kinases in the Src-family, Syk-ZAP-70 family, and BTK family of tyrosine kinases; cytoplasmic serine/threonine kinases and their regulatory subunits such as PIK3CA, PIK3R1, and RAF (e.g., RAF-1, A-RAF, B-RAF); regulatory GTPases such as RAS (e.g., KRAS); transcription factors such as MYC; and combinations thereof.
- growth factors or mitogens such as c-Sis
- receptor tyrosine kinases such as EGFR, HER2, PDGFR, and VEGFR
- KRAS mutation includes any one or more mutations in the KRAS (which can also be referred to as KRAS2 or RASK2) gene.
- KRAS mutations include, but are not limited to, G12S, G12D, G12A, G12V, G12R, G12C, G13D, and combinations thereof.
- BRAF mutation includes any one or more mutations in the BRAF (which can also be referred to as serine/threonine-protein kinase B-Raf or B-Raf) gene.
- BRAF mutations include, but are not limited to, V600E, R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, K600E, A727V, and combinations thereof.
- PIK3CA mutation includes any one or more mutations in the PIK3CA (which can also be referred to as PI3K or p110-alpha) gene.
- PIK3CA mutations include, but are not limited to, E545A, E545G, E545K, Q546E, Q546K, H1047R, H1047L, 3204insA, and combinations thereof.
- EGFR mutation includes any one or more mutations in the EGFR (which can also be referred to as HER1 or ErbB1) gene.
- Examples of EGFR mutations include, but are not limited to, deletions in exon 19 such as L858R, G719S, G719S, G719C, L861Q and S768I, as well as insertions in exon 20 such as T790M, and combinations thereof.
- dilution series is intended to include a series of descending concentrations of a particular sample (e.g., cell lysate) or reagent (e.g., antibody).
- a dilution series is typically produced by a process of mixing a measured amount of a starting concentration of a sample or reagent with a diluent (e.g., dilution buffer) to create a lower concentration of the sample or reagent, and repeating the process enough times to obtain the desired number of serial dilutions.
- a diluent e.g., dilution buffer
- the sample or reagent can be serially diluted at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 500, or 1000-fold to produce a dilution series comprising at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 descending concentrations of the sample or reagent.
- a dilution series comprising a 2-fold serial dilution of a capture antibody reagent at a 1 mg/ml starting concentration
- a dilution series comprising a 2-fold serial dilution of a capture antibody reagent at a 1 mg/ml starting concentration
- a dilution buffer to create a 0.5 mg/ml concentration of the capture antibody, and repeating the process to obtain capture antibody concentrations of 0.25 mg/ml, 0.125 mg/ml, 0.0625 mg/ml, 0.0325 mg/ml, etc.
- the term “superior dynamic range” as used herein refers to the ability of an assay to detect a specific analyte in as few as one cell or in as many as thousands of cells.
- the immunoassays described herein possess superior dynamic range because they advantageously detect a particular signal transduction molecule of interest in about 1-10,000 cells (e.g., about 1, 5, 10, 25, 50, 75, 100, 250, 500, 750, 1000, 2500, 5000, 7500, or 10,000 cells) using a dilution series of capture antibody concentrations.
- sample includes any biological specimen obtained from a patient.
- Samples include, without limitation, whole blood, plasma, serum, red blood cells, white blood cells (e.g., peripheral blood mononuclear cells), ductal lavage fluid, ascites, pleural efflux, nipple aspirate, lymph (e.g., disseminated tumor cells of the lymph node), bone marrow aspirate, saliva, urine, stool (i.e., feces), sputum, bronchial lavage fluid, tears, fine needle aspirate (e.g., harvested by random periareolar fine needle aspiration), any other bodily fluid, a tissue sample (e.g., tumor tissue) such as a biopsy of a tumor (e.g., needle biopsy) or a lymph node (e.g., sentinel lymph node biopsy), a tissue sample (e.g., tumor tissue) such as a surgical resection of a tumor, and cellular extracts thereof
- tissue sample e.
- the sample is whole blood or a fractional component thereof such as plasma, serum, or a cell pellet.
- the sample is obtained by isolating circulating cells of a solid tumor from whole blood or a cellular fraction thereof using any technique known in the art.
- the sample is a formalin fixed paraffin embedded (FFPE) tumor tissue sample, e.g., from a solid tumor such as colorectal cancer.
- FFPE formalin fixed paraffin embedded
- the sample is a tumor lysate or extract prepared from frozen tissue obtained from a subject having colorectal cancer.
- subject or “patient” or “individual” typically includes humans, but can also include other animals such as, e.g., other primates, rodents, canines, felines, equines, ovines, porcines, and the like.
- An “array” or “microarray” comprises a distinct set and/or dilution series of capture antibodies immobilized or restrained on a solid support such as, for example, glass (e.g., a glass slide), plastic, chips, pins, filters, beads (e.g., magnetic beads, polystyrene beads, etc.), paper, membrane (e.g., nylon, nitrocellulose, polyvinylidene fluoride (PVDF), etc.), fiber bundles, or any other suitable substrate.
- the capture antibodies are generally immobilized or restrained on the solid support via covalent or noncovalent interactions (e.g., ionic bonds, hydrophobic interactions, hydrogen bonds, Van der Waals forces, dipole-dipole bonds).
- the capture antibodies comprise capture tags which interact with capture agents bound to the solid support.
- the arrays used in the assays described herein typically comprise a plurality of different capture antibodies and/or capture antibody concentrations that are coupled to the surface of a solid support in different known/addressable locations.
- capture antibody is intended to include an immobilized antibody which is specific for (i.e., binds, is bound by, or forms a complex with) one or more analytes of interest in a sample such as a cellular extract.
- the capture antibody is restrained on a solid support in an array.
- Suitable capture antibodies for immobilizing any of a variety of signal transduction molecules on a solid support are available from Upstate (Temecula, Calif.), Biosource (Camarillo, Calif.), Cell Signaling Technologies (Danvers, Mass.), R&D Systems (Minneapolis, Minn.), Lab Vision (Fremont, Calif.), Santa Cruz Biotechnology (Santa Cruz, Calif.), Sigma (St. Louis, Mo.), and BD Biosciences (San Jose, Calif.).
- detection antibody includes an antibody comprising a detectable label which is specific for (i.e., binds, is bound by, or forms a complex with) one or more analytes of interest in a sample.
- detectable labels include, but are not limited to, biotin/streptavidin labels, nucleic acid (e.g., oligonucleotide) labels, chemically reactive labels, fluorescent labels, enzyme labels, radioactive labels, and combinations thereof.
- Suitable detection antibodies for detecting the activation state and/or total amount of any of a variety of signal transduction molecules are available from Upstate (Temecula, Calif.), Biosource (Camarillo, Calif.), Cell Signaling Technologies (Danvers, Mass.), R&D Systems (Minneapolis, Minn.), Lab Vision (Fremont, Calif.), Santa Cruz Biotechnology (Santa Cruz, Calif.), Sigma (St. Louis, Mo.), and BD Biosciences (San Jose, Calif.).
- phospho-specific antibodies against various phosphorylated forms of signal transduction molecules such as EGFR, c-KIT, c-Src, FLK-1, PDGFRA, PDGFRB, AKT, MAPK, PTEN, Raf, and MEK are available from Santa Cruz Biotechnology.
- activation state-dependent antibody includes a detection antibody which is specific for (i.e., binds, is bound by, or forms a complex with) a particular activation state of one or more analytes of interest in a sample.
- the activation state-dependent antibody detects the phosphorylation, ubiquitination, and/or complexation state of one or more analytes such as one or more signal transduction molecules.
- the phosphorylation of members of the EGFR family of receptor tyrosine kinases and/or the formation of heterodimeric complexes between EGFR family members is detected using activation state-dependent antibodies.
- activation state-dependent antibodies are useful for detecting one or more sites of phosphorylation in one or more of the following signal transduction molecules (phosphorylation sites correspond to the position of the amino acid in the human protein sequence): EGFR/HER1/ErbB1 (e.g., tyrosine (Y) 1068); ErbB2/HER2 (e.g., Y1248); ErbB3/HER3 (e.g., Y1289); ErbB4/HER4 (e.g., Y1284); c-Met (e.g., Y1003, Y1230, Y1234, Y1235, and/or Y1349); SGK3 (e.g., threonine (T) 256 and/or serine (S) 422); 4E-BP1 (e.g., T70); ERK1 (e.g., T185, Y187, T202, and/or Y204); ERK2 (e.g., T185,
- activation state-independent antibody includes a detection antibody which is specific for (i.e., binds, is bound by, or forms a complex with) one or more analytes of interest in a sample irrespective of their activation state.
- the activation state-independent antibody can detect both phosphorylated and unphosphorylated forms of one or more analytes such as one or more signal transduction molecules.
- Receptor tyrosine kinases include a family of fifty-six (56) proteins characterized by a transmembrane domain and a tyrosine kinase motif. RTKs function in cell signaling and transmit signals regulating growth, differentiation, adhesion, migration, and apoptosis. The mutational activation and/or overexpression of receptor tyrosine kinases transforms cells and often plays a crucial role in the development of cancers.
- RTKs have become targets of various molecularly targeted agents such as trastuzumab, cetuximab, gefitinib, erlotinib, sunitinib, imatinib, nilotinib, and the like.
- One well-characterized signal transduction pathway is the MAP kinase pathway, which is responsible for transducing the signal from epidermal growth factor (EGF) to the promotion of cell proliferation in cells.
- EGF epidermal growth factor
- gene and variants thereof includes the segment of DNA involved in producing a polypeptide chain; it includes regions preceding and following the coding region, such as the promoter and 3′-untranslated region, respectively, as well as intervening sequences (introns) between individual coding segments (exons).
- genotyp and variants thereof refers to the genetic composition of an organism, including, for example, whether a diploid organism is heterozygous or homozygous for one or more variant alleles of interest.
- polymorphism and variants thereof refers to the occurrence of two or more genetically determined alternative sequences or alleles in a population.
- a “polymorphic site” refers to the locus at which divergence occurs. Preferred polymorphic sites have at least two alleles, each occurring at a particular frequency in a population.
- a polymorphic locus may be as small as one base pair (e.g., single nucleotide polymorphism or SNP).
- Polymorphic markers include restriction fragment length polymorphisms, variable number of tandem repeats (VNTR's), hypervariable regions, minisatellites, dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats, simple sequence repeats, and insertion elements such as Alu.
- the first identified allele is arbitrarily designated as the reference allele, and other alleles are designated as alternative alleles, “variant alleles,” or “variances.”
- the allele occurring most frequently in a selected population can sometimes be referred to as the “wild-type” allele. Diploid organisms may be homozygous or heterozygous for the variant alleles.
- the variant allele may or may not produce an observable physical or biochemical characteristic (“phenotype”) in an individual carrying the variant allele.
- phenotype a variant allele may alter the enzymatic activity of a protein encoded by a gene of interest or in the alternative the variant allele may have no effect on the enzymatic activity of an encoded protein.
- single nucleotide polymorphism refers to a change of a single nucleotide within a polynucleotide, including within an allele. This can include the replacement of one nucleotide by another, as well as deletion or insertion of a single nucleotide. Most typically, SNPs are biallelic markers, although tri- and tetra-allelic markers can also exist.
- a nucleic acid molecule comprising SNP A ⁇ C may include a C or A at the polymorphic position.
- haplotype is used, e.g., the genotype of the SNPs in a single DNA strand that are linked to one another.
- haplotype can be used to describe a combination of SNP alleles, e.g., the alleles of the SNPs found together on a single DNA molecule.
- the SNPs in a haplotype can be in linkage disequilibrium with one another.
- the present invention provides compositions and methods for detecting the status (e.g., expression and/or activation levels) of components of signal transduction pathways in tumor cells from a colorectal cancer.
- the present invention further comprises detecting (e.g., genotyping for) the presence (or absence) of one or more somatic mutations (e.g., single nucleotide polymorphisms (SNPs)) in tumor cells from a colorectal cancer.
- the present invention also provides compositions and methods for selecting appropriate therapies to downregulate or shut down one or more deregulated signal transduction pathways.
- certain embodiments of the invention may be used to facilitate the design of personalized therapies based on the particular molecular signature provided by the collection of total and activated signal transduction proteins and/or somatic mutations in a given patient's tumor (e.g., colorectal cancer).
- the present invention provides molecular markers (biomarkers) that enable the determination or prediction of whether a colorectal cancer can respond or is likely to respond favorably to an anticancer drug.
- molecular markers biomarkers
- measuring the level of expression and/or activation of at least one or more of HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, and/or SHC is particularly useful for selecting a suitable anticancer drug and/or identifying or predicting a response thereto in cells such as colorectal cancer cells (e.g., isolated cancer cells from a colorectal tumor).
- the methods of the invention further comprise genotyping for the presence or absence of one or more variant alleles (e.g., somatic mutations) in genes such as KRAS, BRAF, and/or PIK3CA (e.g., at one, two, three, four, five, or more polymorphic sites such as a SNP in one or more of these genes).
- the determination of the presence or absence of the variant allele in conjunction with the determination of the expression level and/or activation level of one or more analytes further aids or improves the selection of a suitable anticancer drug and/or the identification or prediction of a response thereto in cells such as colorectal cancer cells (e.g., isolated cancer cells from a colorectal tumor).
- the present invention provides a method for selecting a suitable anticancer drug for the treatment of a colorectal cancer, the method comprising:
- the present invention provides a method for identifying the response of a colorectal cancer to treatment with an anticancer drug, the method comprising:
- the present invention provides a method for predicting the response of a subject having a colorectal cancer to treatment with an anticancer drug, the method comprising:
- the expression level and/or activation level of the one or more analytes is expressed as a relative fluorescence unit (RFU) value that corresponds to the signal intensity for a particular analyte of interest that is determined using, e.g., a proximity assay such as the Collaborative Enzyme Enhanced Reactive Immunoassay (CEERTM) described herein.
- a proximity assay such as the Collaborative Enzyme Enhanced Reactive Immunoassay (CEERTM) described herein.
- CEERTM Collaborative Enzyme Enhanced Reactive Immunoassay
- the expression level and/or activation level of the one or more analytes is expressed as “ ⁇ ”, “ ⁇ ”, “+”, “++”, “+++”, or “++++” that corresponds to increasing signal intensity for a particular analyte of interest that is determined using, e.g., a proximity assay such as CEERTM.
- an undetectable or minimally detectable level of expression or activation of a particular analyte of interest that is determined using, e.g., a proximity assay such as CEERTM may be expressed as “ ⁇ ” or “ ⁇ ”.
- a low level of expression or activation of a particular analyte of interest that is determined using, e.g., a proximity assay such as CEERTM may be expressed as “+”.
- a moderate level of expression or activation of a particular analyte of interest that is determined using, e.g., a proximity assay such as CEERTM may be expressed as “++”.
- a high level of expression or activation of a particular analyte of interest that is determined using, e.g., a proximity assay such as CEERTM may be expressed as “+++”.
- a very high level of expression or activation of a particular analyte of interest that is determined using, e.g., a proximity assay such as CEERTM may be expressed as “++++”.
- the expression level and/or activation level of the one or more analytes is quantitated by calibrating or normalizing the RFU value that is determined using, e.g., a proximity assay such as CEERTM, against a standard curve generated for the particular analyte of interest.
- a computed units (CU) value can be calculated based upon the standard curve.
- the CU value can be expressed as “ ⁇ ”, “ ⁇ ”, “+”, “++”, “+++”, or “++++” in accordance with the description above for signal intensity.
- Example 3 provides a non-limiting example of data analysis for the quantitation of signal transduction pathway proteins in cells such as cancer cells.
- the expression or activation level of a particular analyte of interest when expressed as “ ⁇ ”, “ ⁇ ”, “+”, “++”, “+++”, or “++++”, may correspond to a level of expression or activation that is at least about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 100-fold higher or lower (e.g., about 1.5-3, 2-3, 2-4, 2-5, 2-10, 2-20, 2-50, 3-5, 3-10, 3-20, 3-50, 4-5, 4-10, 4-20, 4-50, 5-10, 5-15, 5-20, or 5-50-fold higher or lower) than a reference expression level or activation level, e.g., when compared to a negative control such as an IgG control, when compared to a standard curve generated for the analyte of interest, when compared to a positive control such as a pan-CK control, when
- the correlation is analyte-specific.
- a “+” level of expression or activation determined using, e.g., a proximity assay such as CEERTM may correspond to a 2-fold increase in expression or activation for one analyte and a 5-fold increase for another analyte when compared to a reference expression or activation level.
- the cancer cell is isolated from a subject having the colorectal cancer after administration of an anticancer drug to the subject.
- the isolated cancer cell is contacted with an anticancer drug.
- the suitable anticancer drug may be selected by comparing the expression level and/or activation level of the one or more analytes to a reference expression and/or activation profile of the one or more analytes generated in the absence of the anticancer drug.
- the colorectal cancer has metastasized.
- step (b) comprises applying the expression level and/or activation level of the one or more analytes determined in step (a) to select a suitable anticancer drug for the treatment of the colorectal cancer, to identify the response of the colorectal cancer to treatment with an anticancer drug, or to predict the response of a subject having the colorectal cancer to treatment with an anticancer drug.
- the methods of the invention further comprise genotyping nucleic acid obtained from the cancer cell to determine the presence or absence of a variant allele in an oncogene.
- the methods of the present invention further comprise the following step:
- the genotyping step (a′) comprises analyzing the cellular extract to determine the presence or absence of a variant allele (e.g., SNP) in one or more oncogenes such as KRAS, BRAF, PIK3CA, and/or EGFR.
- a variant allele e.g., SNP
- oncogenes such as KRAS, BRAF, PIK3CA, and/or EGFR.
- step (b) of the methods of the present invention comprise selecting a suitable anticancer drug for the treatment of the colorectal cancer, identifying the response of the colorectal cancer to treatment with an anticancer drug, or predicting the response of a subject having the colorectal cancer to treatment with an anticancer drug based upon the expression level and/or activation level of the one or more analytes determined in step (a) in combination with the presence or absence of the one or more variant alleles (e.g., somatic mutations) at the one or more polymorphic sites in the one or more oncogenes genotyped in step (a′).
- a suitable anticancer drug for the treatment of the colorectal cancer identifying the response of the colorectal cancer to treatment with an anticancer drug, or predicting the response of a subject having the colorectal cancer to treatment with an anticancer drug based upon the expression level and/or activation level of the one or more analytes determined in step (a) in combination with the presence or absence
- a variant allele e.g., somatic mutation
- Assays that can be used to determine somatic mutation or variant allele status include, but are not limited to, electrophoretic analysis, restriction length polymorphism analysis, sequence analysis, hybridization analysis, PCR analysis, allele-specific hybridization, oligonucleotide ligation allele-specific elongation/ligation, allele-specific amplification, single-base extension, molecular inversion probe, invasive cleavage, selective termination, restriction length polymorphism, sequencing, single strand conformation polymorphism (SSCP), single strand chain polymorphism, mismatch-cleaving, denaturing gradient gel electrophoresis, and combinations thereof.
- electrophoretic analysis restriction length polymorphism analysis
- sequence analysis sequence analysis
- hybridization analysis PCR analysis
- allele-specific hybridization oligonucleotide ligation allele-specific elongation/ligation
- allele-specific amplification single-base extension
- the presence or absence of one or more variant alleles (e.g., one or more somatic mutations) in one or more genes of interest is determined using a genotyping assay as described in U.S. Provisional Application No. 61/525,137, filed Aug. 18, 2011, and U.S. Provisional Application No. 61/588,151, filed Jan. 18, 2012, the disclosures of which are herein incorporated by reference in their entirety for all purposes.
- the methods of the present invention may be useful to aid or assist in the selection of a suitable anticancer drug for the treatment of a colorectal tumor, to identify the response of a colorectal cancer to treatment with an anticancer drug, or to predict the response of a subject having a colorectal cancer to treatment with an anticancer drug.
- the methods of the invention may be useful for improving the selection of a suitable anticancer drug for the treatment of a colorectal tumor, to identify the response of a colorectal cancer to treatment with an anticancer drug, or to predict the response of a subject having a colorectal cancer to treatment with an anticancer drug.
- the present invention provides a method for selecting a suitable anticancer drug for the treatment of a colorectal cancer, the method comprising:
- the present invention provides a method for selecting a suitable anticancer drug for the treatment of a colorectal cancer, the method comprising:
- the present invention provides a method for identifying the response of a colorectal cancer to treatment with an anticancer drug, the method comprising:
- the present invention provides a method for identifying the response of a colorectal cancer to treatment with an anticancer drug, the method comprising:
- the present invention provides a method for predicting the response of a subject having a colorectal cancer to treatment with an anticancer drug, the method comprising:
- the present invention provides a method for predicting the response of a subject having a colorectal cancer to treatment with an anticancer drug, the method comprising:
- the methods of the invention further comprise genotyping nucleic acid obtained from the cancer cell to determine the presence or absence of a variant allele in an oncogene.
- the methods of the present invention further comprise the following step:
- the genotyping step (c′) comprises analyzing the cellular extract to determine the presence or absence of a variant allele (e.g., SNP) in one or more oncogenes such as KRAS, BRAF, PIK3CA, and/or EGFR.
- a variant allele e.g., SNP
- the comparison of step (d) is used in combination with the genotyping of step (c′) to determine whether the anticancer drug is suitable or unsuitable for the treatment of the colorectal cancer, to identify whether the colorectal cancer is responsive or non-responsive to treatment with the anticancer drug, or to predict the likelihood that the subject having the colorectal cancer will respond to treatment with the anticancer drug.
- the methods of the present invention may further comprise a step of providing the result of the comparison obtained in step (d) to a user (e.g., a clinician such as an oncologist or a general practitioner) in a readable format.
- the method may further comprise sending or reporting the result of the comparison obtained in step (d) to a clinician, e.g., an oncologist or a general practitioner.
- the method may further comprise recording or storing the result of the comparison obtained in step (d) in a computer database or other suitable machine or device for storing information, e.g., at a laboratory.
- the expression (e.g., total) level and/or activation (e.g., phosphorylation) level of the one or more analytes is considered to be “changed” in the presence of an anticancer drug when it is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% more or less activated than in the absence of the anticancer drug.
- the expression (e.g., total) level and/or activation (e.g., phosphorylation) level of the one or more analytes is considered to be “substantially decreased” in the presence of an anticancer drug when it is at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% less activated than in the absence of the anticancer drug.
- the expression (e.g., total) level and/or activation (e.g., phosphorylation) level of the one or more analytes is considered to be “substantially decreased” in the presence of an anticancer drug (1) when there is a change from high or strong expression and/or activation of the analyte without the anticancer drug to medium, weak, low, or very weak expression and/or activation of the analyte with the anticancer drug, or (2) when there is a change from medium expression and/or activation of the analyte without the anticancer drug to weak, low, or very weak expression and/or activation of the analyte with the anticancer drug.
- signal transduction proteins are typically extracted shortly after the cells are isolated, preferably within 96, 72, 48, 24, 6, or 1 hr, more preferably within 30, 15, or 5 minutes.
- the isolated cells may also be incubated with growth factors usually at nanomolar to micromolar concentrations for about 1-30 minutes to resuscitate or stimulate signal transducer activation (see, e.g., Irish et al., Cell, 118:217-228 (2004)).
- Stimulatory growth factors include epidermal growth factor (EGF), heregulin (HRG), TGF- ⁇ , PIGF, angiopoietin (Ang), NRG1, PGF, TNF- ⁇ , VEGF, PDGF, IGF, FGF, HGF, cytokines, and the like.
- EGF epidermal growth factor
- HRG heregulin
- TGF- ⁇ PIGF
- Ang angiopoietin
- NRG1 PGF
- TNF- ⁇ VEGF
- PDGF vascular endothelial growth factor
- IGF fibroblast growth factor
- FGF FGF
- HGF cytokines
- the cells are lysed to extract the signal transduction proteins using any technique known in the art.
- the cell lysis is initiated between about 1-360 minutes after growth factor stimulation, and more preferably at two different time intervals: (1) at about 1-5 minutes after growth factor stimulation; and (2) between about 30-180 minutes after growth factor stimulation.
- the lysate can be stored at ⁇ 80° C. until use.
- the anticancer drug comprises an agent that interferes with the function of one or more activated signal transduction pathway components in cancer cells.
- agents include those listed below in Table 1.
- the anticancer drug comprises an anti-signaling agent (i.e., a cytostatic drug) such as a monoclonal antibody or a tyrosine kinase inhibitor; an anti-proliferative agent; a chemotherapeutic agent (i.e., a cytotoxic drug); a hormonal therapeutic agent; a radiotherapeutic agent; a vaccine; and/or any other compound with the ability to reduce or abrogate the uncontrolled growth of aberrant cells such as cancerous cells.
- the isolated cells are treated with one or more anti-signaling agents, anti-proliferative agents, and/or hormonal therapeutic agents in combination with at least one chemotherapeutic agent.
- anti-signaling agents suitable for use in the present invention include, without limitation, monoclonal antibodies such as trastuzumab (HERCEPTIN®), pertuzumab (2C4; PERJATA®), alemtuzumab (CAMPATH®), bevacizumab (AVASTIN®), cetuximab (ERBITUX®), gemtuzumab (MYLOTARG®), panitumumab (VECTIBIXTM), rituximab (RITUXAN®), and tositumomab (BEXXAR®); tyrosine kinase inhibitors such as gefitinib (IRESSA®), sunitinib (SUTENT®), erlotinib (TARCEVA®), lapatinib (GW-572016; TYKERB®), canertinib (CI 1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), soraf
- anti-proliferative agents include mTOR inhibitors such as sirolimus (rapamycin), temsirolimus (CCI-779), everolimus (RAD001), BEZ235, and XL765; AKT inhibitors such as 1L6-hydroxymethyl-chiro-inositol-2-(R)-2-O-methyl-3-O-octadecyl-sn-glycerocarbonate, 9-methoxy-2-methylellipticinium acetate, 1,3-dihydro-1-(1-((4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)phenyl)methyl)-4-piperidinyl)-2H-benzimidazol-2-one, 10-(4′-(N-diethylamino)butyl)-2-chlorophenoxazine, 3-formylchromone thiosemicarbazone (Cu(II)Cl 2 complex), API-2,
- PI3K inhibitors such as PX-866, wortmannin, LY 294002, quercetin, tetrodotoxin citrate, thioperamide maleate, GDC-0941 (957054-30-7), IC87114, PI-103, PIK93, BEZ235 (NVP-BEZ235), TGX-115, ZSTK474, ( ⁇ )-deguelin, NU 7026, myricetin, tandutinib, GDC-0941 bismesylate, GSK690693, KU-55933, MK-2206, OSU-03012, perifosine, triciribine, XL-147, PIK75
- pan-HER inhibitors include PF-00299804, neratinib (HKI-272), AC480 (BMS-599626), BMS-690154, PF-02341066, HM781-36B, CI-1033, BIBW-2992, and combinations thereof.
- Non-limiting examples of chemotherapeutic agents include platinum-based drugs (e.g., oxaliplatin, cisplatin, carboplatin, spiroplatin, iproplatin, satraplatin, etc.), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, etc.), anti-metabolites (e.g., 5-fluorouracil, azathioprine, 6-mercaptopurine, methotrexate, leucovorin, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine (GEMZAR®), pemetrexed (ALIMTA®), raltitrexed, etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine,
- hormonal therapeutic agents include, without limitation, aromatase inhibitors (e.g., aminoglutethimide, anastrozole (ARIMIDEX®), letrozole (FEMARA®), vorozole, exemestane (AROMASIN®), 4-androstene-3,6,17-trione (6-OXO), 1,4,6-androstatrien-3,17-dione (ATD), formestane (LENTARON®), etc.), selective estrogen receptor modulators (e.g., apeledoxifene, clomifene, fulvestrant, lasofoxifene, raloxifene, tamoxifen, toremifene, etc.), steroids (e.g., dexamethasone), finasteride, and gonadotropin-releasing hormone agonists (GnRH) such as goserelin, pharmaceutically acceptable salts thereof, stereoisomers thereof, derivatives thereof, analogs thereof, and combinations thereof.
- Non-limiting examples of cancer vaccines useful in the present invention include ANYARATM (naptumomab estafenatox) from Active Biotech, DCVax-LB from Northwest Biotherapeutics, EP-2101 from IDM Pharma, GV1001 from Pharmexa, 10-2055 from Idera Pharmaceuticals, INGN 225 from Introgen Therapeutics and STIMUVAX® (tecemotide) from Biomira/Merck.
- ANYARATM neuromab estafenatox
- DCVax-LB from Northwest Biotherapeutics
- EP-2101 from IDM Pharma
- GV1001 from Pharmexa
- 10-2055 from Idera Pharmaceuticals
- INGN 225 from Introgen Therapeutics
- STIMUVAX® detectemotide
- radiotherapeutic agents include, but are not limited to, radionuclides such as 47 Sc, 64 Cu, 67 Cu, 89 Sr, 86 Y, 87 Y, 90 Y, 105 Rh, 111 Ag, 111 In, 117m Sn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, and 212 Bi, optionally conjugated to antibodies directed against tumor antigens.
- radionuclides such as 47 Sc, 64 Cu, 67 Cu, 89 Sr, 86 Y, 87 Y, 90 Y, 105 Rh, 111 Ag, 111 In, 117m Sn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, and 212 Bi, optionally conjugated to antibodies directed against tumor antigens.
- Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (HERCEPTIN®) and pertuzumab (2C4; PERJATA®); small molecule tyrosine kinase inhibitors such as gefitinib (IRESSA®), erlotinib (TARCEVA®), pelitinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; TYKERB®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, JNJ-26483327, and JNJ-26483327; and combinations thereof.
- HERCEPTIN® trastuzumab
- 2C4 pertuzumab
- PERJATA® pertuzumab
- small tyrosine kinase inhibitors such as gefitin
- Non-limiting examples of c-Met inhibitors include monoclonal antibodies such as AMG102 and MetMAb; small molecule inhibitors of c-Met such as ARQ197, JNJ-38877605, PF-04217903, SGX523, GSK 1363089/XL880, XL184, MGCD265, and MK-2461; and combinations thereof.
- a reference expression or activation level of the one or more analytes is obtained from a normal cell such as a non-cancerous cell from a healthy individual not having a cancer such as colorectal cancer. In certain other embodiments, a reference expression or activation level of the one or more analytes is obtained from a tumor cell such as a colorectal cancer cell from a patient with a cancer such as colorectal cancer.
- the reference expression or activation level of the one or more analytes is obtained from a cell (e.g., a tumor cell such as a colorectal cell obtained from a sample) that is not treated with the anticancer drug.
- a cell e.g., a tumor cell such as a colorectal cell obtained from a sample
- the cell that is not treated with the anticancer drug is obtained from the same sample that the isolated cell (e.g., a test cell to be interrogated) that is used to produce the cellular extract is obtained.
- the presence of a lower level of expression or activation of the one or more analytes compared to the reference expression or activation level indicates that the anticancer drug is suitable for the treatment of the colorectal cancer (e.g., the colorectal tumor has an increased likelihood of response to the anticancer drug).
- the presence of an identical, similar, or higher level of expression or activation of the one or more analytes compared to the reference expression or activation level indicates that the anticancer drug is unsuitable for the treatment of the colorectal cancer (e.g., the colorectal tumor has a decreased likelihood of response to the anticancer drug).
- the reference expression or activation level of the one or more analytes is obtained from a cell sensitive to the anticancer drug that is treated with the anticancer drug.
- the presence of an identical, similar, or lower level of expression or activation of the one or more analytes compared to the reference expression or activation level indicates that the anticancer drug is suitable for the treatment of the colorectal cancer (e.g., the colorectal tumor has an increased likelihood of response to the anticancer drug).
- the reference expression or activation level of the one or more analytes is obtained from a cell resistant to the anticancer drug that is treated with the anticancer drug.
- the presence of an identical, similar, or higher level of expression or activation of the one or more analytes compared to the reference expression or activation level indicates that the anticancer drug is unsuitable for the treatment of the colorectal cancer (e.g., the colorectal tumor has a decreased likelihood of response to the anticancer drug).
- a higher level of expression or activation of the one or more analytes is considered to be present in a cell or cellular extract when the expression or activation level is at least about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 100-fold higher (e.g., about 1.5-3, 2-3, 2-4, 2-5, 2-10, 2-20, 2-50, 3-5, 3-10, 3-20, 3-50, 4-5, 4-10, 4-20, 4-50, 5-10, 5-15, 5-20, or 5-50-fold higher) than the reference expression or activation level of the corresponding analyte in a cell (e.g., a colorectal cancer cell obtained from a patient sample) not treated with the anticancer drug, in an anticancer drug-sensitive cell treated with the anticancer drug, or in an anticancer drug-resistant cell treated with the anticancer drug.
- a cell e.
- a lower level of expression or activation of the one or more analytes is considered to be present in a cell or cellular extract when the expression or activation level is at least about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 100-fold lower (e.g., about 1.5-3, 2-3, 2-4, 2-5, 2-10, 2-20, 2-50, 3-5, 3-10, 3-20, 3-50, 4-5, 4-10, 4-20, 4-50, 5-10, 5-15, 5-20, or 5-50-fold lower) than the reference expression or activation level of the corresponding analyte in a cell (e.g., a colorectal cancer cell obtained from a patient sample) not treated with the anticancer drug, in an anticancer drug-sensitive cell treated with the anticancer drug, or in an anticancer drug-resistant cell treated with the anticancer drug.
- a cell e.
- Non-limiting examples of signal transduction molecules and pathways that may be interrogated using the present invention include those shown in Table 2.
- Non-limiting examples of analytes such as signal transduction molecules that can be interrogated for expression (e.g., total amount) levels and/or activation (e.g., phosphorylation) levels in a cellular extract include receptor tyrosine kinases, non-receptor tyrosine kinases, tyrosine kinase signaling cascade components, nuclear hormone receptors, nuclear receptor coactivators, nuclear receptor repressors, and combinations thereof.
- the methods of the present invention comprise determining the expression level (e.g., total amount) and/or activation level (e.g., level of phosphorylation or complex formation) of at least one or more of the following analytes in a cellular extract: (1) HER1/EGFR/ErbB1; (2) HER2/ErbB2; (3) p95HER2 (truncated HER2); (4) HER3/ErbB3; (5) c-Met; (6) IGF1R; (7) cKit; (8) PI3K (e.g., PIK3CA and/or PIK3R1); (9) Shc; (10) Akt; (11) p70S6K; (12) VEGFR (e.g., VEGFR1, VEGFR2, and/or VEGFR3) and/or PDGFR (e.g., PDGFRA and/or PDGFRB); and (13) Erk (e.g., Erkl (MAPK3) and/or Erk2 (
- activation level e.g., level of phosphorylation or complex formation
- the combination of five analytes may comprise one of the following: 1,2,3,4,5; 2,3,4,5,6; 3,4,5,6,7; 4,5,6,7,8; 5,6,7,8,9; 6,7,8,9,10; 7,8,9,10,11; 8,9,10,11,12; or 9,10,11,12,13.
- activation level e.g., level of phosphorylation or complex formation
- the combination of six analytes may comprise one of the following: 1,2,3,4,5,6; 2,3,4,5,6,7; 3,4,5,6,7,8; 4,5,6,7,8,9; 5,6,7,8,9,10; 6,7,8,9,10,11; 7,8,9,10,11,12; or 8,9,10,11,12,13.
- activation level e.g., level of phosphorylation or complex formation
- the combination of seven analytes may comprise one of the following: 1,2,3,4,5,6,7; 2,3,4,5,6,7,8; 3,4,5,6,7,8,9; 4,5,6,7,8,9,10; 5,6,7,8,9,10,11; 6,7,8,9,10,11,12; or 7,8,9,10,11,12,13.
- activation level e.g., level of phosphorylation or complex formation
- the combination of eight analytes may comprise one of the following: 1,2,3,4,5,6,7,8; 2,3,4,5,6,7,8,9; 3,4,5,6,7,8,9,10; 4,5,6,7,8,9,10,11; 5,6,7,8,9,10,11,12; or 6,7,8,9,10,11,12,13.
- activation level e.g., level of phosphorylation or complex formation
- the combination of nine analytes may comprise one of the following: 1,2,3,4,5,6,7,8,9; 2,3,4,5,6,7,8,9,10; 3,4,5,6,7,8,9,10,11; 4,5,6,7,8,9,10,11,12; or 5,6,7,8,9,10,11,12,13.
- activation level e.g., level of phosphorylation or complex formation
- the combination of ten analytes may comprise one of the following: 1,2,3,4,5,6,7,8,9,10; 2,3,4,5,6,7,8,9,10,11; 3,4,5,6,7,8,9,10,11,12; or 4,5,6,7,8,9,10,11,12,13.
- alytes e.g., total amount
- activation level e.g., level of phosphorylation or complex formation
- the combination of eleven analytes may comprise one of the following: 1,2,3,4,5,6,7,8,9,10,11; 2,3,4,5,6,7,8,9,10,11,12; or 3,4,5,6,7,8,9,10,11,12,13.
- the combination of twelve analytes may comprise one of the following: 1,2,3,4,5,6,7,8,9,10,11,12; or 2,3,4,5
- activation level e.g., level of phosphorylation or complex formation
- the present invention comprises determining the expression level (e.g., total amount) and/or activation level (e.g., level of phosphorylation or complex formation) of at least one, two, three, four, five, six, seven, eight, nine, or ten of the following analytes: HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K (e.g., PIK3CA and/or PIK3R1), AKT, ERK (e.g., ERK1 (MAPK3) and/or ERK2 (MAPK1)), and SHC.
- HER1, HER2, HER3, cMET e.g., cKIT
- IGF-1R e.g., PIK3CA and/or PIK3R1
- AKT ERK
- ERK e.g., ERK1 (MAPK3) and/or ERK2 (MAPK1)
- SHC SHC
- the present invention comprises (i) determining the expression level of at least one or more of HER1, HER2, HER3, cMET, cKIT, and/or IGF-1R and/or (ii) determining the activation level of at least one or more of HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, and/or SHC.
- the activation level corresponds to a level of phosphorylation of HER1, HER2, HER3, cMET, cKIT, IGF-1R, AKT, ERK, and/or SHC.
- the activation level corresponds to a level of a PI3K complex.
- PI3K complexes include, without limitation, one or more complexes comprising a dimerized receptor tyrosine kinase pair, a PI3K p85 subunit (e.g., PIK3R1), and a PI3K p110 subunit (e.g., an ⁇ or ⁇ subunit such as PIK3CA or PIK3CB); see, for example, U.S. Provisional Application No. 61/530,621, filed Sep. 2, 2011, the disclosure of which is herein incorporated by reference in its entirety for all purposes.
- the present invention further comprises determining the expression level (e.g., total amount) and/or activation level (e.g., level of phosphorylation or complex formation) of one or more (e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, or more) additional analytes in a cellular extract.
- the expression level e.g., total amount
- activation level e.g., level of phosphorylation or complex formation
- the one or more comprises one or more signal transduction molecules selected from the group consisting of receptor tyrosine kinases, non-receptor tyrosine kinases, tyrosine kinase signaling cascade components, nuclear hormone receptors, nuclear receptor coactivators, nuclear receptor repressors, and combinations thereof.
- the present invention further comprises determining the expression level (e.g., total amount) and/or activation level (e.g., level of phosphorylation or complex formation) of one or any combination of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, or more of the following additional analytes in a cellular extract: HER4, MEK, PTEN, SGK3, 4E-BP1, PDK1, PDK2, GSK-3 ⁇ , Raf, SRC, NFkB-IkB, mTOR, EPH-A, EPH-B, EPH-C, EPH-D, FLT-3, TIE-1, TIE-2, c-FMS, Abl, FTL 3, RET, FGFR1, FGFR2, FGFR3, FGFR4, ER, PR, NCOR, MB 1, RON, PIP2, PIP3, p27, protein tyrosine phosphatases (e.g.,
- the present invention provides methods for the rational selection of one or a combination of anticancer drugs tailored to target one or more signal transduction pathway components with higher levels of expression and/or activation detected in a cancer cell obtained from a patient with a somatic mutation in an oncogene.
- the methods of the present invention rely on the detection or measurement of higher levels of expression and/or activation of non-ErbB receptor tyrosine kinases (RTKs) such as cMET and IGF1R in KRAS mutant patients compared to KRAS wild-type patients.
- RTKs non-ErbB receptor tyrosine kinases
- the present invention enables the identification of KRAS mutant patients with both ErbB-driven and ErbB-independent RTK expression and/or activation who would benefit from combination therapy and the selection of appropriate therapies targeting ErbB RTKs (e.g., HER1, HER2, HER3, and/or HER4) and non-ErbB RTKs (e.g., cMET and/or IGF1R).
- ErbB RTKs e.g., HER1, HER2, HER3, and/or HER4
- non-ErbB RTKs e.g., cMET and/or IGF1R
- the present invention provides a method for determining whether an anticancer drug targeting one or more non-ErbB receptor tyrosine kinases (RTKs) should be administered for the treatment of colorectal cancer in a subject with a KRAS mutation, the method comprising:
- a higher expression level or activation level of one or more non-ErbB RTKs is considered to be present in the cancer cell from the KRAS mutant subject when the expression or activation level is at least about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 100-fold higher (e.g., about 1.5-3, 2-3, 2-4, 2-5, 2-10, 2-20, 2-50, 3-5, 3-10, 3-20, 3-50, 4-5, 4-10, 4-20, 4-50, 5-10, 5-15, 5-20, or 5-50-fold higher) than the expression level or activation level of the same non-ErbB RTKs in the cancer cell from the KRAS wild-type subject.
- a higher expression level or activation level of one or more non-ErbB RTKs is considered to be present in the cancer cell from the KRAS mutant subject when there is a statistically significant difference between the expression or activation level of the same non-ErbB RTKs in the KRAS mutant subject compared to the KRAS wild-type subject.
- the differences can be considered as being statistically significant when the P value is less than about 0.1 (e.g., P ⁇ 0.1, P ⁇ 0.05, P ⁇ 0.01, P ⁇ 0.005, P ⁇ 0.001, etc.).
- the one or more non-ErbB RTKs include, but are not limited to, cMET, IGF1R, FGFRs (e.g., FGFR1, FGFR2, FGFR3, and/or FGFR4), VEGFRs (e.g., VEGFR1, VEGFR2, and/or VEGFR3), and combinations thereof.
- the expression level of cMET and/or IGF1R is higher in the cancer cell obtained from the KRAS mutant subject compared to the cancer cell from the KRAS wild-type subject.
- the activation level of cMET is higher in the cancer cell obtained from the KRAS mutant subject compared to the cancer cell obtained from the KRAS wild-type subject.
- the KRAS mutation is selected from the group consisting of G12S, G12D, G12A, G12V, G12R, G12C, G13D, and combinations thereof.
- the cancer cell is a circulating tumor cell (CTC) or a fine needle aspirate (FNA) cell obtained from a colorectal tumor.
- the tumor is primary tumor tissue or metastatic tumor tissue.
- the method further comprises detecting the expression level and/or activation level of one or more ErbB receptor tyrosine kinases (RTKs).
- RTKs ErbB receptor tyrosine kinases
- the expression level and/or activation level of the one or more ErbB RTKs is higher in the cancer cell obtained from the KRAS mutant subject as compared to a reference expression level and/or activation level of the same ErbB RTKs, e.g., in a cancer cell from a KRAS wild-type subject, in a normal (e.g., non-cancerous) cell from a KRAS mutant subject, etc.
- the one or more ErbB RTKs include, but are not limited to, HER1, HER2, HER3, HER4, and combinations thereof.
- the method further comprises determining that an anticancer drug targeting one or more ErbB RTKs should be administered to the subject.
- the anticancer drug targeting one or more non-ErbB RTKs and/or targeting one or more ErbB RTKs includes, but is not limited to, any of the anticancer drugs described herein, such as, e.g., monoclonal antibodies, tyrosine kinase inhibitors, anti-proliferative agents, chemotherapeutic agents, and combinations thereof.
- a combination of ErbB RTK-targeting therapy with cMET-targeting therapy e.g., one or more cMET inhibitors
- the method further comprises administering the anticancer drug targeting one or more of the non-ErbB RTKs to the KRAS mutant subject when a higher expression or activation level of the non-ErbB RTKs is detected compared to the expression or activation level of the same non-ErbB RTKs in the cancer cell from the KRAS wild-type subject.
- the method can further comprise administering the anticancer drug targeting one or more of the ErbB RTKs to the subject when a higher expression or activation level of the ErbB RTKs is detected compared to the expression or activation level of the same ErbB RTKs.
- determining the expression level of the one or more analytes comprises detecting the total amount of each of the one or more analytes in the cellular extract with one or more antibodies specific for the corresponding analyte.
- the antibodies bind to the analyte irrespective of the activation state of the analyte to be detected, i.e., the antibodies detect both the non-activated and activated forms of the analyte.
- Total expression level and/or status can be determined using any of a variety of techniques.
- the total expression level and/or status of each of the one or more analytes such as signal transduction molecules in a sample is detected with an immunoassay such as a single detection assay or a proximity dual detection assay (e.g., a Collaborative Enzyme Enhanced Reactive Immunoassay (CEERTM)) as described herein.
- an immunoassay such as a single detection assay or a proximity dual detection assay (e.g., a Collaborative Enzyme Enhanced Reactive Immunoassay (CEERTM)) as described herein.
- CEERTM Collaborative Enzyme Enhanced Reactive Immunoassay
- determining the expression (e.g., total) levels of the one or more analytes comprises:
- determining the expression (e.g., total) levels of the one or more analytes that are truncated receptors comprises:
- the first activation state-independent antibodies may be directly labeled with the facilitating moiety or indirectly labeled with the facilitating moiety, e.g., via hybridization between an oligonucleotide conjugated to the first activation state-independent antibodies and a complementary oligonucleotide conjugated to the facilitating moiety.
- the second activation state-independent antibodies may be directly labeled with the first member of the signal amplification pair or indirectly labeled with the first member of the signal amplification pair, e.g., via binding between a first member of a binding pair conjugated to the second activation state-independent antibodies and a second member of the binding pair conjugated to the first member of the signal amplification pair.
- the first member of the binding pair is biotin and the second member of the binding pair is an avidin such as streptavidin or neutravidin.
- the facilitating moiety may be, for example, glucose oxidase.
- the glucose oxidase and the first activation state-independent antibodies can be conjugated to a sulfhydryl-activated dextran molecule as described in, e.g., Examples 16-17 of PCT Publication No. WO2009/108637, the disclosure of which is herein incorporated by reference in its entirety for all purposes.
- the sulfhydryl-activated dextran molecule typically has a molecular weight of about 500 kDa (e.g., about 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or 750 kDa).
- the oxidizing agent may be, for example, hydrogen peroxide (H 2 O 2 ).
- the first member of the signal amplification pair may be, for example, a peroxidase such as horseradish peroxidase (HRP).
- the second member of the signal amplification pair may be, for example, a tyramide reagent (e.g., biotin-tyramide).
- the amplified signal is generated by peroxidase oxidization of biotin-tyramide to produce an activated tyramide (e.g., to transform the biotin-tyramide into an activated tyramide).
- the activated tyramide may be directly detected or indirectly detected, e.g., upon the addition of a signal-detecting reagent.
- signal-detecting reagents include streptavidin-labeled fluorophores and combinations of streptavidin-labeled peroxidases and chromogenic reagents such as, e.g., 3,3′,5,5′-tetramethylbenzidine (TMB).
- the horseradish peroxidase and the second activation state-independent antibodies can be conjugated to a sulfhydryl-activated dextran molecule.
- the sulfhydryl-activated dextran molecule typically has a molecular weight of about 70 kDa (e.g., about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 kDa).
- the truncated receptor is typically a fragment of the full-length receptor and shares an intracellular domain (ICD) binding region with the full-length receptor.
- the full-length receptor comprises an extracellular domain (ECD) binding region, a transmembrane domain, and an intracellular domain (ICD) binding region.
- ECD extracellular domain
- ICD intracellular domain
- the truncated receptor may arise through the proteolytic processing of the ECD of the full-length receptor or by alternative initiation of translation from methionine residues that are located before, within, or after the transmembrane domain, e.g., to create a truncated receptor with a shortened ECD or a truncated receptor comprising a membrane-associated or cytosolic ICD fragment.
- the truncated receptor is p95HER2 and the corresponding full-length receptor is HER2.
- the methods described herein for detecting truncated proteins can be applied to a number of different proteins including, but not limited to, the EGFR VIII mutant (implicated in glioblastoma, colorectal cancer, etc.), other truncated receptor tyrosine kinases, caspases, and the like.
- WO2009/108637 provides an exemplary embodiment of the assay methods of the present invention for detecting truncated receptors such as p95HER2 in cells using a multiplex, high-throughput, proximity dual detection microarray ELISA having superior dynamic range.
- the plurality of beads specific for an ECD binding region comprises a streptavidin-biotin pair, wherein the streptavidin is attached to the bead and the biotin is attached to an antibody.
- the antibody is specific for the ECD binding region of the full-length receptor (e.g., full-length HER2).
- each dilution series of capture antibodies comprises a series of descending capture antibody concentrations.
- the capture antibodies are serially diluted at least 2-fold (e.g., 2, 5, 10, 20, 50, 100, 500, or 1000-fold) to produce a dilution series comprising a set number (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more) of descending capture antibody concentrations which are spotted onto an array.
- a set number e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more
- at least 2, 3, 4, 5, or 6 replicates of each capture antibody dilution are spotted onto the array.
- the solid support comprises glass (e.g., a glass slide), plastic, chips, pins, filters, beads, paper, membrane (e.g., nylon, nitrocellulose, polyvinylidene fluoride (PVDF), etc.), fiber bundles, or any other suitable substrate.
- the capture antibodies are restrained (e.g., via covalent or noncovalent interactions) on glass slides coated with a nitrocellulose polymer such as, for example, FAST® Slides, which are commercially available from Whatman Inc. (Florham Park, N.J.). Exemplary methods for constructing antibody arrays suitable for use in the invention are described, e.g., in PCT Publication No. WO2009/108637, the disclosure of which is herein incorporated by reference in its entirety for all purposes.
- determining the activation levels of the one or more analytes comprises detecting a phosphorylation level of the one or more analytes in the cellular extract with antibodies specific for the phosphorylated form of each of the analytes to be detected.
- Phosphorylation levels and/or status can be determined using any of a variety of techniques. For example, it is well known in the art that phosphorylated proteins can be detected via immunoassays using antibodies that specifically recognize the phosphorylated form of the protein (see, e.g., Lin et al., Br. J. Cancer, 93:1372-1381 (2005)). Immunoassays generally include immunoblotting (e.g., Western blotting), RIA, and ELISA. More specific types of immunoassays include antigen capture/antigen competition, antibody capture/antigen competition, two-antibody sandwiches, antibody capture/antibody excess, and antibody capture/antigen excess.
- Phospho-specifc antibodies can be made de novo or obtained from commercial or noncommercial sources. Phosphorylation levels and/or status can also be determined by metabolically labeling cells with radioactive phosphate in the form of [ ⁇ - 32 P]ATP or [ ⁇ - 33 P]ATP. Phosphorylated proteins become radioactive and hence traceable and quantifiable through scintillation counting, radiography, and the like (see, e.g., Wang et al., J. Biol. Chem., 253:7605-7608 (1978)).
- metabolically labeled proteins can be extracted from cells, separated by gel electrophoresis, transferred to a membrane, probed with an antibody specific for a particular analyte and subjected to autoradiography to detect 32 P or 33 P.
- the gel can be subjected to autoradiography prior to membrane transference and antibody probing.
- the activation (e.g., phosphorylation) level and/or status of each of the one or more analytes in a sample is detected with an immunoassay such as a single detection assay or a proximity dual detection assay (e.g., a Collaborative Enzyme Enhanced Reactive Immunoassay (CEERTM)) as described herein.
- an immunoassay such as a single detection assay or a proximity dual detection assay (e.g., a Collaborative Enzyme Enhanced Reactive Immunoassay (CEERTM)) as described herein.
- determining the activation (e.g., phosphorylation) level of the one or more analytes comprises:
- determining the activation (e.g., phosphorylation) level of the one or more analytes that are truncated receptors comprises:
- the activation state-independent antibodies may be directly labeled with the facilitating moiety or indirectly labeled with the facilitating moiety, e.g., via hybridization between an oligonucleotide conjugated to the activation state-independent antibodies and a complementary oligonucleotide conjugated to the facilitating moiety.
- the activation state-dependent antibodies may be directly labeled with the first member of the signal amplification pair or indirectly labeled with the first member of the signal amplification pair, e.g., via binding between a first member of a binding pair conjugated to the activation state-dependent antibodies and a second member of the binding pair conjugated to the first member of the signal amplification pair.
- the first member of the binding pair is biotin and the second member of the binding pair is an avidin such as streptavidin or neutravidin.
- the facilitating moiety may be, for example, glucose oxidase.
- the glucose oxidase and the activation state-independent antibodies can be conjugated to a sulfhydryl-activated dextran molecule as described in, e.g., Examples 16-17 of PCT Publication No. WO2009/108637, the disclosure of which is herein incorporated by reference in its entirety for all purposes.
- the sulfhydryl-activated dextran molecule typically has a molecular weight of about 500 kDa (e.g., about 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or 750 kDa).
- the oxidizing agent may be, for example, hydrogen peroxide (H 2 O 2 ).
- the first member of the signal amplification pair may be, for example, a peroxidase such as horseradish peroxidase (HRP).
- the second member of the signal amplification pair may be, for example, a tyramide reagent (e.g., biotin-tyramide).
- the amplified signal is generated by peroxidase oxidization of biotin-tyramide to produce an activated tyramide (e.g., to transform the biotin-tyramide into an activated tyramide).
- the activated tyramide may be directly detected or indirectly detected, e.g., upon the addition of a signal-detecting reagent.
- signal-detecting reagents include streptavidin-labeled fluorophores and combinations of streptavidin-labeled peroxidases and chromogenic reagents such as, e.g., 3,3′,5,5′-tetramethylbenzidine (TMB).
- the horseradish peroxidase and the activation state-dependent antibodies can be conjugated to a sulfhydryl-activated dextran molecule.
- the sulfhydryl-activated dextran molecule typically has a molecular weight of about 70 kDa (e.g., about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 kDa).
- the truncated receptor is typically a fragment of the full-length receptor and shares an intracellular domain (ICD) binding region with the full-length receptor.
- the full-length receptor comprises an extracellular domain (ECD) binding region, a transmembrane domain, and an intracellular domain (ICD) binding region.
- ECD extracellular domain
- ICD intracellular domain
- the truncated receptor may arise through the proteolytic processing of the ECD of the full-length receptor or by alternative initiation of translation from methionine residues that are located before, within, or after the transmembrane domain, e.g., to create a truncated receptor with a shortened ECD or a truncated receptor comprising a membrane-associated or cytosolic ICD fragment.
- the truncated receptor is p95HER2 and the corresponding full-length receptor is HER2.
- the methods described herein for detecting truncated proteins can be applied to a number of different proteins including, but not limited to, the EGFR VIII mutant (implicated in glioblastoma, colorectal cancer, etc.), other truncated receptor tyrosine kinases, caspases, and the like.
- WO2009/108637 provides an exemplary embodiment of the assay methods of the present invention for detecting truncated receptors such as p95HER2 in cells using a multiplex, high-throughput, proximity dual detection microarray ELISA having superior dynamic range.
- the plurality of beads specific for an ECD binding region comprises a streptavidin-biotin pair, wherein the streptavidin is attached to the bead and the biotin is attached to an antibody.
- the antibody is specific for the ECD binding region of the full-length receptor (e.g., full-length HER2).
- each dilution series of capture antibodies comprises a series of descending capture antibody concentrations.
- the capture antibodies are serially diluted at least 2-fold (e.g., 2, 5, 10, 20, 50, 100, 500, or 1000-fold) to produce a dilution series comprising a set number (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more) of descending capture antibody concentrations which are spotted onto an array.
- a set number e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more
- at least 2, 3, 4, 5, or 6 replicates of each capture antibody dilution are spotted onto the array.
- the solid support comprises glass (e.g., a glass slide), plastic, chips, pins, filters, beads, paper, membrane (e.g., nylon, nitrocellulose, polyvinylidene fluoride
- the capture antibodies are restrained (e.g., via covalent or noncovalent interactions) on glass slides coated with a nitrocellulose polymer such as, for example, FAST® Slides, which are commercially available from Whatman Inc. (Florham Park, N.J.).
- a nitrocellulose polymer such as, for example, FAST® Slides, which are commercially available from Whatman Inc. (Florham Park, N.J.).
- FAST® Slides which are commercially available from Whatman Inc. (Florham Park, N.J.).
- Exemplary methods for constructing antibody arrays suitable for use in the invention are described, e.g., in PCT Publication No. WO2009/108637, the disclosure of which is herein incorporated by reference in its entirety for all purposes.
- the assay for detecting the expression and/or activation level of one or more analytes of interest in a cellular extract of cells such as tumor cells is a multiplex, high-throughput two-antibody assay having superior dynamic range.
- the two antibodies used in the assay can comprise: (1) a capture antibody specific for a particular analyte of interest; and (2) a detection antibody specific for an activated form of the analyte (i.e., activation state-dependent antibody).
- the activation state-dependent antibody is capable of detecting, for example, the phosphorylation, ubiquitination, and/or complexation state of the analyte.
- the detection antibody comprises an activation state-independent antibody, which detects the total amount of the analyte in the cellular extract.
- the activation state-independent antibody is generally capable of detecting both the activated and non-activated forms of the analyte.
- the two-antibody assay for detecting the expression or activation level of an analyte of interest comprises:
- the two-antibody assays described herein are typically antibody-based arrays which comprise a plurality of different capture antibodies at a range of capture antibody concentrations that are coupled to the surface of a solid support in different addressable locations. Examples of suitable solid supports for use in the present invention are described above.
- the capture antibodies and detection antibodies are preferably selected to minimize competition between them with respect to analyte binding (i.e., both capture and detection antibodies can simultaneously bind their corresponding signal transduction molecules).
- the detection antibodies comprise a first member of a binding pair (e.g., biotin) and the first member of the signal amplification pair comprises a second member of the binding pair (e.g., streptavidin).
- the binding pair members can be coupled directly or indirectly to the detection antibodies or to the first member of the signal amplification pair using methods well-known in the art.
- the first member of the signal amplification pair is a peroxidase (e.g., horseradish peroxidase (HRP), catalase, chloroperoxidase, cytochrome c peroxidase, eosinophil peroxidase, glutathione peroxidase, lactoperoxidase, myeloperoxidase, thyroid peroxidase, deiodinase, etc.), and the second member of the signal amplification pair is a tyramide reagent (e.g., biotin-tyramide).
- the amplified signal is generated by peroxidase oxidization of the tyramide reagent to produce an activated tyramide in the presence of hydrogen peroxide (H 2 O 2 ).
- the activated tyramide is either directly detected or detected upon the addition of a signal-detecting reagent such as, for example, a streptavidin-labeled fluorophore or a combination of a streptavidin-labeled peroxidase and a chromogenic reagent.
- a signal-detecting reagent such as, for example, a streptavidin-labeled fluorophore or a combination of a streptavidin-labeled peroxidase and a chromogenic reagent.
- fluorophores suitable for use in the present invention include, but are not limited to, an Alexa Fluor® dye (e.g., Alexa Fluor® 555), fluorescein, fluorescein isothiocyanate (FITC), Oregon Green®; rhodamine, Texas red, tetrarhodamine isothiocynate (TRITC), a CyDyeTM fluor (e.g., Cy2, Cy3, Cy5), and the like.
- Alexa Fluor® dye e.g., Alexa Fluor® 555
- fluorescein fluorescein isothiocyanate
- FITC fluorescein isothiocyanate
- TRITC rhodamine
- CyDyeTM fluor e.g., Cy2, Cy3, Cy5
- Non-limiting examples of chromogenic reagents suitable for use in the present invention include 3,3′,5,5′-tetramethylbenzidine (TMB), 3,3′-diaminobenzidine (DAB), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 4-chloro-1-napthol (4CN), and/or porphyrinogen.
- TMB 3,3′,5,5′-tetramethylbenzidine
- DAB 3,3′-diaminobenzidine
- ABTS 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)
- 4CN 4-chloro-1-napthol
- the present invention provides a method for detecting the expression or activation level of a truncated receptor, the method comprising:
- the truncated receptor is p95HER2 and the full-length receptor is HER2.
- the plurality of beads specific for an extracellular domain (ECD) binding region comprises a streptavidin-biotin pair, wherein the biotin is attached to the bead and the biotin is attached to an antibody (e.g., wherein the antibody is specific for the ECD binding region of the full-length receptor).
- FIG. 14A of PCT Publication No. WO2009/108637 shows that beads coated with an antibody directed to the extracellular domain (ECD) of a receptor of interest binds the full-length receptor (e.g., HER2), but not the truncated receptor (e.g., p95HER2) to remove any full-length receptor from the assay.
- FIG. 14B of PCT Publication No. WO2009/108637 shows that the truncated receptor (e.g., p95HER2), once bound to a capture antibody, may then be detected by a detection antibody that is specific for the intracellular domain (ICD) of the full-length receptor (e.g., HER2).
- ICD intracellular domain
- the detection antibody may be directly conjugated to horseradish peroxidase (HRP). Tyramide signal amplification (TSA) may then be performed to generate a signal to be detected.
- TSA horseradish peroxidase
- the expression level or activation state of the truncated receptor e.g., p95HER2
- p95HER2 can be interrogated to determine, e.g., its total concentration or its phosphorylation state, ubiquitination state, and/or complexation state.
- kits for performing the two-antibody assays described above comprising: (a) a dilution series of one or a plurality of capture antibodies restrained on a solid support; and (b) one or a plurality of detection antibodies (e.g., activation state-independent antibodies and/or activation state-dependent antibodies).
- the kits can further contain instructions for methods of using the kit to detect the expression levels and/or activation states of one or a plurality of signal transduction molecules of cells such as tumor cells.
- kits may also contain any of the additional reagents described above with respect to performing the specific methods of the present invention such as, for example, first and second members of the signal amplification pair, tyramide signal amplification reagents, wash buffers, etc.
- the assay for detecting the expression and/or activation level of one or more analytes of interest in a cellular extract of cells such as tumor cells is a multiplex, high-throughput proximity (i.e., three-antibody) assay having superior dynamic range.
- the three antibodies used in the proximity assay can comprise: (1) a capture antibody specific for a particular analyte of interest; (2) a detection antibody specific for an activated form of the analyte (i.e., activation state-dependent antibody); and (3) a detection antibody which detects the total amount of the analyte (i.e., activation state-independent antibody).
- the activation state-dependent antibody is capable of detecting, e.g., the phosphorylation, ubiquitination, and/or complexation state of the analyte, while the activation state-independent antibody is capable of detecting the total amount (i.e., both the activated and non-activated forms) of the analyte.
- the proximity assay for detecting the activation level or status of an analyte of interest comprises:
- the proximity assay for detecting the activation level or status of an analyte of interest that is a truncated receptor comprises:
- the truncated receptor is p95HER2 and the full-length receptor is HER2.
- the plurality of beads specific for an extracellular domain (ECD) binding region comprises a streptavidin-biotin pair, wherein the biotin is attached to the bead and the biotin is attached to an antibody (e.g., wherein the antibody is specific for the ECD binding region of the full-length receptor).
- the activation state-dependent antibodies can be labeled with a facilitating moiety and the activation state-independent antibodies can be labeled with a first member of a signal amplification pair.
- the three antibodies used in the proximity assay can comprise: (1) a capture antibody specific for a particular analyte of interest; (2) a first detection antibody which detects the total amount of the analyte (i.e., a first activation state-independent antibody); and (3) a second detection antibody which detects the total amount of the analyte (i.e., a second activation state-independent antibody).
- the first and second activation state-independent antibodies recognize different (e.g., distinct) epitopes on the analyte.
- the proximity assay for detecting the expression level of an analyte of interest comprises:
- the proximity assay for detecting the expression level of an analyte of interest that is a truncated receptor comprises:
- the truncated receptor is p95HER2 and the full-length receptor is HER2.
- the plurality of beads specific for an extracellular domain (ECD) binding region comprises a streptavidin-biotin pair, wherein the biotin is attached to the bead and the biotin is attached to an antibody (e.g., wherein the antibody is specific for the ECD binding region of the full-length receptor).
- the first activation state-independent antibodies can be labeled with a first member of a signal amplification pair and the second activation state-independent antibodies can be labeled with a facilitating moiety.
- the proximity assays described herein are typically antibody-based arrays which comprise one or a plurality of different capture antibodies at a range of capture antibody concentrations that are coupled to the surface of a solid support in different addressable locations. Examples of suitable solid supports for use in the present invention are described above.
- the capture antibodies, activation state-independent antibodies, and activation state-dependent antibodies are preferably selected to minimize competition between them with respect to analyte binding (i.e., all antibodies can simultaneously bind their corresponding signal transduction molecules).
- activation state-independent antibodies for detecting activation levels of one or more of the analytes or, alternatively, first activation state-independent antibodies for detecting expression levels of one or more of the analytes further comprise a detectable moiety.
- the amount of the detectable moiety is correlative to the amount of one or more of the analytes in the cellular extract.
- detectable moieties include, but are not limited to, fluorescent labels, chemically reactive labels, enzyme labels, radioactive labels, and the like.
- the detectable moiety is a fluorophore such as an ALEXA FLUOR® dye (e.g., ALEXA FLUOR® 647), fluorescein, fluorescein isothiocyanate (FITC), OREGON GREEN®; rhodamine, Texas red, tetrarhodamine isothiocynate (TRITC), a CYDYETM fluor (e.g., Cy2, Cy3, Cy5), and the like.
- ALEXA FLUOR® dye e.g., ALEXA FLUOR® 647
- FITC fluorescein isothiocyanate
- OREGON GREEN® OREGON GREEN®
- rhodamine Texas red
- tetrarhodamine isothiocynate a CYDYETM fluor
- the detectable moiety can be coupled directly or
- activation state-independent antibodies for detecting activation levels of one or more of the analytes or, alternatively, first activation state-independent antibodies for detecting expression levels of one or more of the analytes are directly labeled with the facilitating moiety.
- the facilitating moiety can be coupled to activation state-independent antibodies using methods well-known in the art.
- a suitable facilitating moiety for use in the present invention includes any molecule capable of generating an oxidizing agent which channels to (i.e., is directed to) and reacts with (i.e., binds, is bound by, or forms a complex with) another molecule in proximity (i.e., spatially near or close) to the facilitating moiety.
- facilitating moieties include, without limitation, enzymes such as glucose oxidase or any other enzyme that catalyzes an oxidation/reduction reaction involving molecular oxygen (O 2 ) as the electron acceptor, and photosensitizers such as methylene blue, rose bengal, porphyrins, squarate dyes, phthalocyanines, and the like.
- oxidizing agents include hydrogen peroxide (H 2 O 2 ), a singlet oxygen, and any other compound that transfers oxygen atoms or gains electrons in an oxidation/reduction reaction.
- the facilitating moiety e.g., glucose oxidase, photosensitizer, etc.
- an oxidizing agent e.g., hydrogen peroxide (H 2 O 2 ), single oxygen, etc.
- HRP horseradish peroxidase
- hapten protected by a protecting group e.g., an enzyme inactivated by thioether linkage to an enzyme inhibitor, etc.
- activation state-independent antibodies for detecting activation levels of one or more of the analytes or, alternatively, first activation state-independent antibodies for detecting expression levels of one or more of the analytes are indirectly labeled with the facilitating moiety via hybridization between an oligonucleotide linker conjugated to the activation state-independent antibodies and a complementary oligonucleotide linker conjugated to the facilitating moiety.
- the oligonucleotide linkers can be coupled to the facilitating moiety or to the activation state-independent antibodies using methods well-known in the art.
- the oligonucleotide linker conjugated to the facilitating moiety has 100% complementarity to the oligonucleotide linker conjugated to the activation state-independent antibodies.
- the oligonucleotide linker pair comprises at least one, two, three, four, five, six, or more mismatch regions, e.g., upon hybridization under stringent hybridization conditions.
- activation state-independent antibodies specific for different analytes can either be conjugated to the same oligonucleotide linker or to different oligonucleotide linkers.
- the length of the oligonucleotide linkers that are conjugated to the facilitating moiety or to the activation state-independent antibodies can vary.
- the linker sequence can be at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, or 100 nucleotides in length.
- random nucleic acid sequences are generated for coupling.
- a library of oligonucleotide linkers can be designed to have three distinct contiguous domains: a spacer domain; signature domain; and conjugation domain.
- the oligonucleotide linkers are designed for efficient coupling without destroying the function of the facilitating moiety or activation state-independent antibodies to which they are conjugated.
- the oligonucleotide linker sequences can be designed to prevent or minimize any secondary structure formation under a variety of assay conditions. Melting temperatures are typically carefully monitored for each segment within the linker to allow their participation in the overall assay procedures. Generally, the range of melting temperatures of the segment of the linker sequence is between 1-10° C. Computer algorithms (e.g., OLIGO 6.0) for determining the melting temperature, secondary structure, and hairpin structure under defined ionic concentrations can be used to analyze each of the three different domains within each linker.
- Computer algorithms e.g., OLIGO 6.0
- the overall combined sequences can also be analyzed for their structural characterization and their comparability to other conjugated oligonucleotide linker sequences, e.g., whether they will hybridize under stringent hybridization conditions to a complementary oligonucleotide linker.
- the spacer region of the oligonucleotide linker provides adequate separation of the conjugation domain from the oligonucleotide crosslinking site.
- the conjugation domain functions to link molecules labeled with a complementary oligonucleotide linker sequence to the conjugation domain via nucleic acid hybridization.
- the nucleic acid-mediated hybridization can be performed either before or after antibody-analyte (i.e., antigen) complex formation, providing a more flexible assay format.
- antibody-analyte i.e., antigen
- the signature sequence domain of the oligonucleotide linker can be used in complex multiplexed protein assays. Multiple antibodies can be conjugated with oligonucleotide linkers with different signature sequences. In multiplex immunoassays, reporter oligonucleotide sequences labeled with appropriate probes can be used to detect cross-reactivity between antibodies and their antigens in the multiplex assay format.
- Oligonucleotide linkers can be conjugated to antibodies or other molecules using several different methods. For example, oligonucleotide linkers can be synthesized with a thiol group on either the 5′ or 3′ end. The thiol group can be deprotected using reducing agents (e.g., TCEP-HCl) and the resulting linkers can be purified by using a desalting spin column. The resulting deprotected oligonucleotide linkers can be conjugated to the primary amines of antibodies or other types of proteins using heterobifunctional cross linkers such as SMCC.
- reducing agents e.g., TCEP-HCl
- 5′-phosphate groups on oligonucleotides can be treated with water-soluble carbodiimide EDC to form phosphate esters and subsequently coupled to amine-containing molecules.
- the diol on the 3′-ribose residue can be oxidized to aldehyde groups and then conjugated to the amine groups of antibodies or other types of proteins using reductive amination.
- the oligonucleotide linker can be synthesized with a biotin modification on either the 3′ or 5′ end and conjugated to streptavidin-labeled molecules.
- Oligonucleotide linkers can be synthesized using any of a variety of techniques known in the art, such as those described in Usman et al., J. Am. Chem. Soc., 109:7845 (1987); Scaringe et al., Nucl. Acids Res., 18:5433 (1990); Wincott et al., Nucl. Acids Res., 23:2677-2684 (1995); and Wincott et al., Methods Mol. Bio., 74:59 (1997).
- oligonucleotides makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end and phosphoramidites at the 3′-end.
- Suitable reagents for oligonucleotide synthesis, methods for nucleic acid deprotection, and methods for nucleic acid purification are known to those of skill in the art.
- activation state-dependent antibodies for detecting activation levels of one or more of the analytes or, alternatively, second activation state-independent antibodies for detecting expression levels of one or more of the analytes are directly labeled with the first member of the signal amplification pair.
- the signal amplification pair member can be coupled to activation state-dependent antibodies to detect activation levels or second activation state-independent antibodies to detect expression levels using methods well-known in the art.
- activation state-dependent antibodies or second activation state-independent antibodies are indirectly labeled with the first member of the signal amplification pair via binding between a first member of a binding pair conjugated to the activation state-dependent antibodies or second activation state-independent antibodies and a second member of the binding pair conjugated to the first member of the signal amplification pair.
- the binding pair members e.g., biotin/streptavidin
- signal amplification pair members include, but are not limited to, peroxidases such horseradish peroxidase (HRP), catalase, chloroperoxidase, cytochrome c peroxidase, eosinophil peroxidase, glutathione peroxidase, lactoperoxidase, myeloperoxidase, thyroid peroxidase, deiodinase, and the like.
- HRP horseradish peroxidase
- catalase chloroperoxidase
- chloroperoxidase cytochrome c peroxidase
- eosinophil peroxidase glutathione peroxidase
- lactoperoxidase lactoperoxidase
- myeloperoxidase myeloperoxidase
- thyroid peroxidase deiodinase
- signal amplification pair members include haptens protected by a protecting group and enzymes inactivated by
- the facilitating moiety is glucose oxidase (GO) and the first member of the signal amplification pair is horseradish peroxidase (HRP).
- HRP horseradish peroxidase
- the GO When the GO is contacted with a substrate such as glucose, it generates an oxidizing agent (i.e., hydrogen peroxide (H 2 O 2 )).
- the H 2 O 2 generated by the GO is channeled to and complexes with the HRP to form an HRP-H 2 O 2 complex, which, in the presence of the second member of the signal amplification pair (e.g., a chemiluminescent substrate such as luminol or isoluminol or a fluorogenic substrate such as tyramide (e.g., biotin-tyramide), homovanillic acid, or 4-hydroxyphenyl acetic acid), generates an amplified signal.
- the second member of the signal amplification pair e.g., a chemiluminescent substrate such as luminol or isoluminol or a fluorogenic substrate such as tyramide (e.g., biotin-tyramide), homovanillic acid, or 4-hydroxyphenyl acetic acid.
- the HRP-H 2 O 2 complex oxidizes the tyramide to generate a reactive tyramide radical that covalently binds nearby nucleophilic residues.
- the activated tyramide is either directly detected or detected upon the addition of a signal-detecting reagent such as, for example, a streptavidin-labeled fluorophore or a combination of a streptavidin-labeled peroxidase and a chromogenic reagent.
- fluorophores suitable for use in the present invention include, but are not limited to, an ALEXA FLUOR® dye (e.g., ALEXA FLUOR® 555), fluorescein, fluorescein isothiocyanate (FITC), OREGON GREEN®; rhodamine, Texas red, tetrarhodamine isothiocynate (TRITC), a CYDYETM fluor (e.g., Cy2, Cy3, Cy5), and the like.
- the streptavidin label can be coupled directly or indirectly to the fluorophore or peroxidase using methods well-known in the art.
- Non-limiting examples of chromogenic reagents suitable for use in the present invention include 3,3′,5,5′-tetramethylbenzidine (TMB), 3,3′-diaminobenzidine (DAB), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 4-chloro-1-napthol (4CN), and/or porphyrinogen.
- TMB 3,3′,5,5′-tetramethylbenzidine
- DAB 3,3′-diaminobenzidine
- ABTS 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)
- 4CN 4-chloro-1-napthol
- the facilitating moiety is a photosensitizer and the first member of the signal amplification pair is a large molecule labeled with multiple haptens that are protected with protecting groups that prevent binding of the haptens to a specific binding partner (e.g., ligand, antibody, etc.).
- the signal amplification pair member can be a dextran molecule labeled with protected biotin, coumarin, and/or fluorescein molecules.
- Suitable protecting groups include, but are not limited to, phenoxy-, analino-, olefin-, thioether-, and selenoether-protecting groups.
- the unprotected haptens are then available to specifically bind to the second member of the signal amplification pair (e.g., a specific binding partner that can generate a detectable signal).
- the specific binding partner can be an enzyme-labeled streptavidin.
- Exemplary enzymes include alkaline phosphatase, ⁇ -galactosidase, HRP, etc.
- the detectable signal can be generated by adding a detectable (e.g., fluorescent, chemiluminescent, chromogenic, etc.) substrate of the enzyme and detected using suitable methods and instrumentation known in the art.
- the detectable signal can be amplified using tyramide signal amplification and the activated tyramide either directly detected or detected upon the addition of a signal-detecting reagent as described above.
- the facilitating moiety is a photosensitizer and the first member of the signal amplification pair is an enzyme-inhibitor complex.
- the enzyme and inhibitor e.g., phosphonic acid-labeled dextran
- a cleavable linker e.g., thioether
- the photosensitizer When excited with light, it generates an oxidizing agent (i.e., singlet oxygen).
- the enzyme-inhibitor complex is within channeling proximity to the photosensitizer, the singlet oxygen generated by the photosensitizer is channeled to and reacts with the cleavable linker, releasing the inhibitor from the enzyme, thereby activating the enzyme.
- An enzyme substrate is added to generate a detectable signal, or alternatively, an amplification reagent is added to generate an amplified signal.
- the facilitating moiety is HRP
- the first member of the signal amplification pair is a protected hapten or an enzyme-inhibitor complex as described above
- the protecting groups comprise p-alkoxy phenol.
- the addition of phenylenediamine and H 2 O 2 generates a reactive phenylene diimine which channels to the protected hapten or the enzyme-inhibitor complex and reacts with p-alkoxy phenol protecting groups to yield exposed haptens or a reactive enzyme.
- the amplified signal is generated and detected as described above (see, e.g., U.S. Pat. Nos. 5,532,138 and 5,445,944).
- kits for performing the proximity assays described above comprising: (a) a dilution series of one or a plurality of capture antibodies restrained on a solid support; and (b) one or a plurality of detection antibodies (e.g., a combination of activation state-independent antibodies and activation state-dependent antibodies for detecting activation levels and/or a combination of first and second activation state-independent antibodies for detecting expression levels).
- the kits can further contain instructions for methods of using the kit to detect the expression and/or activation status of one or a plurality of signal transduction molecules of cells such as tumor cells.
- kits may also contain any of the additional reagents described above with respect to performing the specific methods of the present invention such as, for example, first and second members of the signal amplification pair, tyramide signal amplification reagents, substrates for the facilitating moiety, wash buffers, etc.
- a variety of means can be used to genotype an individual at a polymorphic site in an oncogene such as the KRAS, BRAF, PIK3CA, and/or EGFR gene to determine whether a sample (e.g., a nucleic acid sample) contains a specific variant allele (e.g., somatic mutation) or haplotype.
- a sample e.g., a nucleic acid sample
- a specific variant allele e.g., somatic mutation
- haplotype e.g., somatic mutation
- an individual is genotyped at one, two, three, four, five, or more polymorphic sites such as a single nucleotide polymorphism (SNP) in one or more oncogenes of interest.
- SNP single nucleotide polymorphism
- Genotyping of nucleic acid from an individual, whether amplified or not, can be performed using any of various techniques.
- Useful techniques include, without limitation, assays such as polymerase chain reaction (PCR) based analysis assays, sequence analysis assays, electrophoretic analysis assays, restriction length polymorphism analysis assays, hybridization analysis assays, allele-specific hybridization, oligonucleotide ligation allele-specific elongation/ligation, allele-specific amplification, single-base extension, molecular inversion probe, invasive cleavage, selective termination, restriction length polymorphism, sequencing, single strand conformation polymorphism (SSCP), single strand chain polymorphism, mismatch-cleaving, and denaturing gradient gel electrophoresis, all of which can be used alone or in combination.
- assays such as polymerase chain reaction (PCR) based analysis assays, sequence analysis assays, electrophoretic analysis assays, restriction length polymorphism analysis
- nucleic acid includes a polynucleotide such as a single- or double-stranded DNA or RNA molecule including, for example, genomic DNA, cDNA and mRNA. This term encompasses nucleic acid molecules of both natural and synthetic origin as well as molecules of linear, circular, or branched configuration representing either the sense or antisense strand, or both, of a native nucleic acid molecule. It is understood that such nucleic acids can be unpurified, purified, or attached, for example, to a synthetic material such as a bead or column matrix.
- the presence or absence of a variant allele (e.g., somatic mutation) in one or more oncogenes of interest is determined using a genotyping assay as described in U.S. Provisional Application No. 61/525,137, filed Aug. 18, 2011, and U.S. Provisional Application No. 61/588,151, filed Jan. 18, 2012, the disclosures of which are herein incorporated by reference in their entirety for all purposes.
- Material containing nucleic acid is routinely obtained from individuals. Such material is any biological matter from which nucleic acid can be prepared. As non-limiting examples, material can be whole blood, serum, plasma, saliva, cheek swab, sputum, or other bodily fluid or tissue that contains nucleic acid. In one embodiment, a method of the present invention is practiced with whole blood, which can be obtained readily by non-invasive means and used to prepare genomic DNA. In another embodiment, genotyping involves amplification of an individual's nucleic acid using the polymerase chain reaction (PCR). Use of PCR for the amplification of nucleic acids is well known in the art (see, e.g., Mullis et al.
- PCR polymerase chain reaction
- PCR amplification is performed using one or more fluorescently labeled primers.
- PCR amplification is performed using one or more labeled or unlabeled primers that contain a DNA minor groove binder.
- primers for PCR analysis can be designed based on the sequence flanking the polymorphic site(s) of interest in the gene of interest.
- a sequence primer can contain from about 15 to about 30 nucleotides of a sequence upstream or downstream of the polymorphic site of interest in the gene of interest.
- Such primers generally are designed to have sufficient guanine and cytosine content to attain a high melting temperature which allows for a stable annealing step in the amplification reaction.
- Several computer programs, such as Primer Select are available to aid in the design of PCR primers.
- a TAQMAN® allelic discrimination assay (probe-based quantitative PCT assay for allelic discrimination) available from Applied Biosystems can be useful for genotyping an individual at a polymorphic site to thereby determine the presence or absence of a particular variant allele (e.g., somatic mutation) or haplotype in the gene of interest.
- a TAQMAN® allelic discrimination assay a specific fluorescent dye-labeled probe for each allele is constructed.
- the probes contain different fluorescent reporter dyes such as FAMTM and VIC® to differentiate amplification of each allele.
- each probe has a quencher dye at one end which quenches fluorescence by fluorescence resonance energy transfer.
- each probe anneals specifically to complementary sequences in the nucleic acid from the individual.
- the 5′ nuclease activity of Taq polymerase is used to cleave only probe that hybridizes to the allele. Cleavage separates the reporter dye from the quencher dye, resulting in increased fluorescence by the reporter dye.
- the fluorescence signal generated by PCR amplification indicates which alleles are present in the sample. Mismatches between a probe and allele reduce the efficiency of both probe hybridization and cleavage by Taq polymerase, resulting in little to no fluorescent signal.
- Minor groove binders include, but are not limited to, compounds such as dihydrocyclopyrroloindole tripeptide (DPI3).
- Sequence analysis can also be useful for genotyping an individual according to the methods described herein to determine the presence or absence of a particular variant allele (e.g., somatic mutation) or haplotype in the gene of interest.
- a variant allele of interest can be detected by sequence analysis using the appropriate primers, which are designed based on the sequence flanking the polymorphic site of interest in the gene of interest.
- a variant allele in a gene of interest can be detected by sequence analysis using primers designed by one of skill in the art.
- Additional or alternative sequence primers can contain from about 15 to about 30 nucleotides of a sequence that corresponds to a sequence about 40 to about 400 base pairs upstream or downstream of the polymorphic site of interest in the gene of interest.
- Such primers are generally designed to have sufficient guanine and cytosine content to attain a high melting temperature which allows for a stable annealing step in the sequencing reaction.
- sequence analysis includes any manual or automated process by which the order of nucleotides in a nucleic acid is determined.
- sequence analysis can be used to determine the nucleotide sequence of a sample of DNA.
- sequence analysis encompasses, without limitation, chemical and enzymatic methods such as dideoxy enzymatic methods including, for example, Maxam-Gilbert and Sanger sequencing as well as variations thereof.
- sequence analysis further encompasses, but is not limited to, capillary array DNA sequencing, which relies on capillary electrophoresis and laser-induced fluorescence detection and can be performed using instruments such as the MegaBACE 1000 or ABI PRISM® 3700.
- sequence analysis encompasses thermal cycle sequencing (see, Sears et al., Biotechniques 13:626-633 (1992)); solid-phase sequencing (see, Zimmerman et al., Methods Mol. Cell Biol. 3:39-42 (1992); and sequencing with mass spectrometry, such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (see, MALDI-TOF MS; Fu et al., Nature Biotech. 16:381-384 (1998)).
- sequence analysis further includes, but is not limited to, sequencing by hybridization (SBH), which relies on an array of all possible short oligonucleotides to identify a segment of sequence (see, Chee et al., Science 274:610-614 (1996); Drmanac et al., Science 260:1649-1652 (1993); and Drmanac et al., Nature Biotech. 16:54-58 (1998)).
- SBH sequencing by hybridization
- Electrophoretic analysis also can be useful in genotyping an individual according to the methods of the present invention to determine the presence or absence of a particular variant allele (e.g., somatic mutation) or haplotype in the gene of interest.
- “Electrophoretic analysis” as used herein in reference to one or more nucleic acids such as amplified fragments includes a process whereby charged molecules are moved through a stationary medium under the influence of an electric field. Electrophoretic migration separates nucleic acids primarily on the basis of their charge, which is in proportion to their size, with smaller molecules migrating more quickly.
- the term electrophoretic analysis includes, without limitation, analysis using slab gel electrophoresis, such as agarose or polyacrylamide gel electrophoresis, or capillary electrophoresis.
- Capillary electrophoretic analysis generally occurs inside a small-diameter (50-100 m) quartz capillary in the presence of high (kilovolt-level) separating voltages with separation times of a few minutes.
- nucleic acids are conveniently detected by UV absorption or fluorescent labeling, and single-base resolution can be obtained on fragments up to several hundred base pairs.
- Such methods of electrophoretic analysis, and variations thereof, are well known in the art, as described, for example, in Ausubel et al., Current Protocols in Molecular Biology Chapter 2 (Supplement 45) John Wiley & Sons, Inc. New York (1999).
- Restriction fragment length polymorphism (RFLP) analysis can also be useful for genotyping an individual according to the methods of the present invention to determine the presence or absence of a particular variant allele (e.g., somatic mutation) or haplotype in the gene of interest (see, Jarcho et al. in Dracopoli et al., Current Protocols in Human Genetics pages 2.7.1-2.7.5, John Wiley & Sons, New York; Innis et al., (Ed.), PCR Protocols , San Diego: Academic Press, Inc. (1990)).
- a particular variant allele e.g., somatic mutation
- haplotype in the gene of interest
- restriction fragment length polymorphism analysis includes any method for distinguishing polymorphic alleles using a restriction enzyme, which is an endonuclease that catalyzes degradation of nucleic acid following recognition of a specific base sequence, generally a palindrome or inverted repeat.
- a restriction enzyme which is an endonuclease that catalyzes degradation of nucleic acid following recognition of a specific base sequence, generally a palindrome or inverted repeat.
- RFLP analysis depends upon an enzyme that can differentiate a variant allele from a wild-type or other allele at a polymorphic site.
- allele-specific oligonucleotide hybridization can be useful for genotyping an individual in the methods described herein to determine the presence or absence of a particular variant allele (e.g., somatic mutation) or haplotype in the gene of interest.
- Allele-specific oligonucleotide hybridization is based on the use of a labeled oligonucleotide probe having a sequence perfectly complementary, for example, to the sequence encompassing the variant allele. Under appropriate conditions, the variant allele-specific probe hybridizes to a nucleic acid containing the variant allele but does not hybridize to the one or more other alleles, which have one or more nucleotide mismatches as compared to the probe.
- a second allele-specific oligonucleotide probe that matches an alternate (e.g., wild-type) allele can also be used.
- the technique of allele-specific oligonucleotide amplification can be used to selectively amplify, for example, a variant allele by using an allele-specific oligonucleotide primer that is perfectly complementary to the nucleotide sequence of the variant allele but which has one or more mismatches as compared to other alleles (Mullis et al., supra).
- an allele-specific oligonucleotide primer to be used in PCR amplification generally contains the one or more nucleotide mismatches that distinguish between the variant and other alleles at the 3′ end of the primer.
- a heteroduplex mobility assay is another well-known assay that can be used for genotyping in the methods of the present invention to determine the presence or absence of a particular variant allele (e.g., somatic mutation) or haplotype in the gene of interest.
- HMA is useful for detecting the presence of a variant allele since a DNA duplex carrying a mismatch has reduced mobility in a polyacrylamide gel compared to the mobility of a perfectly base-paired duplex (see, Delwart et al., Science, 262:1257-1261 (1993); White et al., Genomics, 12:301-306 (1992)).
- SSCP single strand conformational polymorphism
- Denaturing gradient gel electrophoresis can also be useful in the methods of the invention to determine the presence or absence of a particular variant allele (e.g., somatic mutation) or haplotype in the gene of interest.
- double-stranded DNA is electrophoresed in a gel containing an increasing concentration of denaturant; double-stranded fragments made up of mismatched alleles have segments that melt more rapidly, causing such fragments to migrate differently as compared to perfectly complementary sequences (see, Sheffield et al., “Identifying DNA Polymorphisms by Denaturing Gradient Gel Electrophoresis” in Innis et al., supra, 1990).
- genotyping approaches include, without limitation, automated sequencing and RNase mismatch techniques (see, Winter et al., Proc. Natl. Acad. Sci., 82:7575-7579 (1985)).
- individual variant alleles can be detected by any combination of molecular methods. See, in general, Birren et al. (Eds.) Genome Analysis: A Laboratory Manual Volume 1 (Analyzing DNA) New York, Cold Spring Harbor Laboratory Press (1997).
- multiple variant alleles can be detected in individual reactions or in a single reaction (a “multiplex” assay).
- the generation and selection of antibodies not already commercially available for analyzing the levels of expression and activation of signal transduction molecules in tumor cells in accordance with the immunoassays of the present invention can be accomplished several ways. For example, one way is to express and/or purify a polypeptide of interest (i.e., antigen) using protein expression and purification methods known in the art, while another way is to synthesize the polypeptide of interest using solid phase peptide synthesis methods known in the art. See, e.g., Guide to Protein Purification , Murray P. Deutcher, ed., Meth. Enzymol. , Vol. 182 (1990); Solid Phase Peptide Synthesis , Greg B. Fields, ed., Meth. Enzymol.
- the purified or synthesized polypeptide can then be injected, for example, into mice or rabbits, to generate polyclonal or monoclonal antibodies.
- One skilled in the art will recognize that many procedures are available for the production of antibodies, for example, as described in Antibodies, A Laboratory Manual , Harlow and Lane, Eds., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1988).
- binding fragments or Fab fragments which mimic (e.g., retain the functional binding regions of) antibodies can also be prepared from genetic information by various procedures. See, e.g., Antibody Engineering: A Practical Approach , Borrebaeck, Ed., Oxford University Press, Oxford (1995); and Huse et al., J. Immunol., 149:3914-3920 (1992).
- the anticancer drugs described herein are administered to a subject by any convenient means known in the art.
- the methods of the present invention can be used to select a suitable anticancer drug or combination of anticancer drugs for the treatment of a tumor, e.g., a colorectal tumor, in a subject.
- the methods of the present invention can also be used to identify the response of a tumor, e.g., a colorectal tumor, in a subject to treatment with an anticancer drug or combination of anticancer drugs.
- the methods of the present invention can be used to predict the response of a subject having a tumor, e.g., a colorectal tumor, to treatment with an anticancer drug or combination of anticancer drugs.
- the anticancer drugs described herein can be administered alone or as part of a combined therapeutic approach with conventional chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and/or surgery.
- the anticancer drug comprises an anti-signaling agent (i.e., a cytostatic drug) such as a monoclonal antibody or a tyrosine kinase inhibitor; an anti-proliferative agent; a chemotherapeutic agent (i.e., a cytotoxic drug); a hormonal therapeutic agent; a radiotherapeutic agent; a vaccine; and/or any other compound with the ability to reduce or abrogate the uncontrolled growth of aberrant cells such as cancerous cells.
- the subject is treated with one or more anti-signaling agents, anti-proliferative agents, and/or hormonal therapeutic agents in combination with at least one chemotherapeutic agent.
- exemplary monoclonal antibodies, tyrosine kinase inhibitors, anti-proliferative agents, chemotherapeutic agents, hormonal therapeutic agents, radiotherapeutic agents, and vaccines are described above.
- the anticancer drugs described herein can be co-administered with conventional immunotherapeutic agents including, but not limited to, immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to 111 In, 90 Y, or 131 I, etc.).
- immunostimulants e.g., Bacillus Calmette-Guérin (BCG), levamisole, interleukin-2, alpha-interferon, etc.
- immunotoxins e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody
- Anticancer drugs can be administered with a suitable pharmaceutical excipient as necessary and can be carried out via any of the accepted modes of administration.
- administration can be, for example, oral, buccal, sublingual, gingival, palatal, intravenous, topical, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intravesical, intrathecal, intralesional, intranasal, rectal, vaginal, or by inhalation.
- co-administer it is meant that an anticancer drug is administered at the same time, just prior to, or just after the administration of a second drug (e.g., another anticancer drug, a drug useful for reducing the side-effects associated with anticancer drug therapy, a radiotherapeutic agent, a hormonal therapeutic agent, an immunotherapeutic agent, etc.).
- a second drug e.g., another anticancer drug, a drug useful for reducing the side-effects associated with anticancer drug therapy, a radiotherapeutic agent, a hormonal therapeutic agent, an immunotherapeutic agent, etc.
- a therapeutically effective amount of an anticancer drug may be administered repeatedly, e.g., at least 2, 3, 4, 5, 6, 7, 8, or more times, or the dose may be administered by continuous infusion.
- the dose may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, pills, pellets, capsules, powders, solutions, suspensions, emulsions, suppositories, retention enemas, creams, ointments, lotions, gels, aerosols, foams, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of an anticancer drug calculated to produce the desired onset, tolerability, and/or therapeutic effects, in association with a suitable pharmaceutical excipient (e.g., an ampoule).
- a suitable pharmaceutical excipient e.g., an ampoule
- more concentrated dosage forms may be prepared, from which the more dilute unit dosage forms may then be produced.
- the more concentrated dosage forms thus will contain substantially more than, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times the amount of the anticancer drug.
- the dosage forms typically include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents, carriers, adjuvants, diluents, tissue permeation enhancers, solubilizers, and the like.
- Appropriate excipients can be tailored to the particular dosage form and route of administration by methods well known in the art (see, e.g., R EMINGTON'S P HARMACEUTICAL S CIENCES , supra).
- excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and polyacrylic acids such as Carbopols, e.g., Carbopol 941, Carbopol 980, Carbopol 981, etc.
- Carbopols e.g., Carbopol 941, Carbopol 980, Carbopol 981, etc.
- the dosage forms can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying agents; suspending agents; preserving agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates (i.e., the parabens); pH adjusting agents such as inorganic and organic acids and bases; sweetening agents; and flavoring agents.
- lubricating agents such as talc, magnesium stearate, and mineral oil
- wetting agents such as talc, magnesium stearate, and mineral oil
- emulsifying agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates (i.e., the parabens)
- pH adjusting agents such as inorganic and organic acids and bases
- sweetening agents and flavoring agents.
- the dosage forms may also comprise biodegradable polymer beads, dextran, and cyclodextrin inclusion complexes.
- the therapeutically effective dose can be in the form of tablets, capsules, emulsions, suspensions, solutions, syrups, sprays, lozenges, powders, and sustained-release formulations.
- Suitable excipients for oral administration include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
- the therapeutically effective dose takes the form of a pill, tablet, or capsule, and thus, the dosage form can contain, along with an anticancer drug, any of the following: a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as starch or derivatives thereof a lubricant such as magnesium stearate and the like; and a binder such a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof.
- An anticancer drug can also be formulated into a suppository disposed, for example, in a polyethylene glycol (PEG) carrier.
- PEG polyethylene glycol
- Liquid dosage forms can be prepared by dissolving or dispersing an anticancer drug and optionally one or more pharmaceutically acceptable adjuvants in a carrier such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension, e.g., for oral, topical, or intravenous administration.
- a carrier such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension, e.g., for oral, topical, or intravenous administration.
- An anticancer drug can also be formulated into a retention enema.
- the therapeutically effective dose can be in the form of emulsions, lotions, gels, foams, creams, jellies, solutions, suspensions, ointments, and transdermal patches.
- an anticancer drug can be delivered as a dry powder or in liquid form via a nebulizer.
- the therapeutically effective dose can be in the form of sterile injectable solutions and sterile packaged powders.
- injectable solutions are formulated at a pH of from about 4.5 to about 7.5.
- the therapeutically effective dose can also be provided in a lyophilized form.
- dosage forms may include a buffer, e.g., bicarbonate, for reconstitution prior to administration, or the buffer may be included in the lyophilized dosage form for reconstitution with, e.g., water.
- the lyophilized dosage form may further comprise a suitable vasoconstrictor, e.g., epinephrine.
- the lyophilized dosage form can be provided in a syringe, optionally packaged in combination with the buffer for reconstitution, such that the reconstituted dosage form can be immediately administered to a subject.
- a subject can also be monitored at periodic time intervals to assess the efficacy of a certain therapeutic regimen. For example, the activation states of certain signal transduction molecules may change based on the therapeutic effect of treatment with one or more of the anticancer drugs described herein. The subject can be monitored to assess response and understand the effects of certain drugs or treatments in an individualized approach. Additionally, subjects who initially respond to a specific anticancer drug or combination of anticancer drugs may become refractory to the drug or drug combination, indicating that these subjects have developed acquired drug resistance. These subjects can be discontinued on their current therapy and an alternative treatment prescribed in accordance with the methods of the present invention.
- the methods described herein can be used in conjunction with panels of gene expression markers that predict the likelihood of colorectal cancer prognosis and/or recurrence in various populations. These gene panels can be useful for identifying individuals who are unlikely to experience recurrence and, thus, unlikely to benefit from adjuvant chemotherapy.
- the expression panels can be used to identify individuals who can safely avoid adjuvant chemotherapy, without negatively affecting disease-free and overall survival outcomes. Suitable systems include, but are not limited to, Oncotype DXTM, which is a 21-gene panel from Genomic Health, Inc.; MammaPrint,® which is a 70-gene panel from Agendia; and a 76-gene panel from Veridex.
- the methods described herein can be used in conjunction with panels of gene expression markers that identify the original tumors for cancers of unknown primary (CUP). These gene panels can be useful in identifying patients with metastatic cancer who would benefit from therapy consistent with that given to patients diagnosed initially with colorectal cancer.
- Suitable systems include, but are not limited to, the Aviara CANCERTYPE ID® assay, an RT-PCR-based expression assay that measures 92 genes to identify the primary site of origin for 39 tumor types; and the PATHWORK® Tissue of Origin Test, which measures the expression of more than 1600 genes on a microarray and compares a tumor's gene expression “signature” against those of 15 known tissue types.
- Colorectal cancer is a leading cause of death in the developed countries.
- the development of effective forms of cytotoxic chemotherapy for colorectal cancer has been paralleled by the emergence of monoclonal antibodies against proteins that are thought to be important in the proliferation of malignant cells.
- Recent clinical studies showed that EGFR-targeting agents improved response rate when added to chemotherapy; however, patients with KRAS mutations did not benefit from such treatment.
- the study provided in this example demonstrates a comprehensive profiling of ErbB proteins as well as ErbB associated signal proteins for their level of expression/activation and the presence of somatic mutations in tumor tissues obtained from 136 CRC patients.
- the Collaborative Enzyme Enhanced Reactive-immunoassay is a multiplexed protein microarray platform requiring co-localization of two detector enzyme-conjugated-antibodies. Once target proteins are captured on the microarray-surface, channeling events between two detector enzymes in proximity enable the profiling of the target proteins with high sensitivity.
- tumor lysates were prepared from frozen tissues obtained from 136 CRC patients.
- the level of expression and activation of HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK and other pathway proteins were determined using the CEERTM technology.
- FIG. 1 provides tables which show that KRAS and BRAF mutations were found in ⁇ 40% (54/136) and ⁇ 5% (6/136), respectively, in this cohort. The most frequent mutant alleles were G12D (14%) and G13D (13%).
- FIG. 2 provides a table showing that varying levels of RTKs and associated activation patterns were observed. Levels of phosphorylated AKT and ERK correlated to expression/activation patterns of HER1, cMET, HER3 and the prevalence of each biomarker can be determined.
- a comprehensive profiling based on multiplexed functional pathway/somatic mutation analysis provides critical information clinicians need to select the most effective targeted agents for combination or sequenced treatments.
- CRC colorectal cancer
- CEERTM Collaborative Enzyme Enhanced Reactive
- CRC samples revealed distribution and frequency of specific oncogenic mutations in primary and metastatic colorectal cancers. As their influence on signaling pathway profiles cannot be predicted based on mutations alone, it is critical to also evaluate pathway activation for a more effective clinical strategy. This study also demonstrated modulation in signaling pathways concomitant with disease recurrence. Such clinical validations and comprehensive molecular profiles of CRC tumors can allow for the implementation of these companion biomarkers in CRC therapeutic clinical trials.
- This example illustrates the quantitation of the expression and/or activation levels of one or more analytes such as one or more signal transduction proteins in a biological sample (e.g., CTC or FNA) against a standard curve generated for the particular analyte of interest.
- a biological sample e.g., CTC or FNA
- each CEERTM slide is scanned at three photomultiplier (PMT) gain settings to improve sensitivity and reduce the impact of saturation.
- Perkin Elmer SCANARRAY® Express software is used for spot finding and signal quantitation. The identifiers for each spot are imported from a GENEPIXTM Array List (.gal) file. The de-identified study specific number for each clinical sample on a slide is incorporated into the resulting data set.
- background corrected signal intensities are averaged for replicate spots printed in triplicate.
- the relative fluorescence value of the respective reagent blank is subtracted from each sample.
- quality criteria are used to filter data from further analysis including limits on the spot footprint, coefficient of variation for spot replicates, overall pad background and the intensity of the reagent blank.
- a sigmoidal standard curve can be generated from multiple (e.g., two, three, four, five, six, seven, etc.) concentrations of serially diluted cell lysates prepared from cell lines such as MD-468 (HER1 positive), SKBr3 (HER2 positive), BT474 (HER2 and p95HER2 positive), HCC827 (c-MET and HER1 positive), T47D stimulated with IGF (IGF1R positive), and/or T47D stimulated with HRG (HER3 positive).
- Each curve can be plotted as a function of signal intensity vs. log concentration derived units, CU (Computed Unit).
- the data can be fit to a five parameter equation (5PL) by nonlinear regression (Ritz, C.
- CU Calculation (based on standard curve)—The individual predictions from each of the standard curves (e.g., 3 capture antibody dilutions and 3 PMT gain-set scanning) can be combined into a single, final prediction.
- the slope of the point on the standard curve is calculated. This slope is taken with log-units on the x-axis, i.e., the units in the denominator of the slope are log Computed Units (CU).
- CU log Computed Units
- Second, a weighted average of the predictions is calculated, where the weights are determined from the slopes. Specifically, the weights are summed, and each point is given a weight equal to its slope divided by the total slopes.
- Each assay can be validated against predictions for known controls.
- CRC colorectal cancer
- RTKs e.g., ErbBs, FGFRs, VEGFRs, cMET, IGF1R, etc.
- non-RTKs e.g., Src, FAK, etc.
- Jak/Stat along with AKT and MAPK pathway proteins
- CEERTM Collaborative Enzyme Enhanced Reactive
- a significant pathway redundancy was detected in most tumors. Furthermore, pathway diversity in tumors with identical mutational background was evident in this analysis. Redundant pathways leading to distinct pathway activation patterns were also determined among the paired primary-metastatic samples.
- CEERTM-based pathway analysis adds value towards an understanding of a CRC tumor's potential response under various clinical scenarios.
- the comprehensive characterization of pathway redundancy allows the rational selection of a combination of targeted agents.
- clinicians can make rational decisions in selecting agents targeting relevant pathway proteins.
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Abstract
Description
-
- (a) determining the expression level and/or activation level of one or more analytes selected from the group consisting of HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, SHC, and combinations thereof in a cellular extract produced from an isolated cancer cell; and
- (b) selecting a suitable anticancer drug for the treatment of the colorectal cancer based upon the expression level and/or activation level of the one or more analytes determined in step (a).
-
- (a) determining the expression level and/or activation level of one or more analytes selected from the group consisting of HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, SHC, and combinations thereof in a cellular extract produced from an isolated cancer cell; and
- (b) identifying the response of the colorectal cancer to treatment with an anticancer drug based upon the expression level and/or activation level of the one or more analytes determined in step (a).
-
- (a) determining the expression level and/or activation level of one or more analytes selected from the group consisting of HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, SHC, and combinations thereof in a cellular extract produced from an isolated cancer cell; and
- (b) predicting the response of the subject having the colorectal cancer to treatment with an anticancer drug based upon the expression level and/or activation level of the one or more analytes determined in step (a).
-
- (a′) genotyping for the presence or absence of a variant allele (e.g., somatic mutation) at a polymorphic site in an oncogene such as KRAS, BRAF, PIK3CA, and/or EGFR (e.g., one or more somatic mutations at one, two, three, four, five, or more polymorphic sites such as a single nucleotide polymorphism (SNP) in one or more of these genes) in a cellular extract produced from an isolated cancer cell (e.g., an aliquot of the cellular extract used in step (a)).
-
- (a) isolating a cancer cell after administration of an anticancer drug, or prior to incubation with an anticancer drug;
- (b) lysing the isolated cell to produce a cellular extract;
- (c) determining the expression level and/or activation level of one or more analytes selected from the group consisting of HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, SHC, and combinations thereof in the cellular extract; and
- (d) comparing the expression level and/or activation level of the one or more analytes determined in step (c) to a reference expression and/or activation profile of the one or more analytes that is generated in the absence of the anticancer drug to determine whether the anticancer drug is suitable or unsuitable for the treatment of the colorectal cancer.
-
- (a) contacting a cancer cell obtained from a sample of the colorectal cancer with an anticancer drug;
- (b) lysing the isolated cell to produce a cellular extract;
- (c) determining the expression level and/or activation level of one or more analytes selected from the group consisting of HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, SHC, and combinations thereof in the cellular extract;
- (d) comparing the expression level and/or activation level of the one or more analytes determined in step (c) to a reference expression and/or activation profile of the one or more analytes that is generated in the absence of the anticancer drug; and
- (e) indicating that the anticancer drug is suitable for the treatment of the colorectal cancer when the expression level and/or activation level determined for the one or more analytes is changed (e.g., substantially decreased) compared to the reference expression and/or activation profile.
-
- (a) isolating a cancer cell after administration of an anticancer drug, or prior to incubation with an anticancer drug;
- (b) lysing the isolated cell to produce a cellular extract;
- (c) determining the expression level and/or activation level of one or more analytes selected from the group consisting of HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, SHC, and combinations thereof in the cellular extract; and
- (d) comparing the expression level and/or activation level of the one or more analytes determined in step (c) to a reference expression and/or activation profile of the one or more analytes that is generated in the absence of the anticancer drug to identify whether the colorectal cancer is responsive or non-responsive to treatment with the anticancer drug.
-
- (a) contacting a cancer cell obtained from a sample of the colorectal cancer with an anticancer drug;
- (b) lysing the isolated cell to produce a cellular extract;
- (c) determining the expression level and/or activation level of one or more analytes selected from the group consisting of HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, SHC, and combinations thereof in the cellular extract;
- (d) comparing the expression level and/or activation level of the one or more analytes determined in step (c) to a reference expression and/or activation profile of the one or more analytes that is generated in the absence of the anticancer drug; and
- (e) indicating that the colorectal cancer is responsive to treatment with the anticancer drug (e.g., the colorectal tumor has an increased likelihood or probability of response to treatment with the anticancer drug) when the expression level and/or activation level determined for the one or more analytes is changed (e.g., substantially decreased) compared to the reference expression and/or activation profile.
-
- (a) isolating a cancer cell after administration of an anticancer drug, or prior to incubation with an anticancer drug;
- (b) lysing the isolated cell to produce a cellular extract;
- (c) determining the expression level and/or activation level of one or more analytes selected from the group consisting of HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, SHC, and combinations thereof in the cellular extract; and
- (d) comparing the expression level and/or activation level of the one or more analytes determined in step (c) to a reference expression and/or activation profile of the one or more analytes that is generated in the absence of the anticancer drug to predict the likelihood that the subject having the colorectal cancer will respond to treatment with the anticancer drug.
-
- (a) contacting a cancer cell obtained from a sample of the colorectal cancer with an anticancer drug;
- (b) lysing the isolated cell to produce a cellular extract;
- (c) determining the expression level and/or activation level of one or more analytes selected from the group consisting of HER1, HER2, HER3, cMET, cKIT, IGF-1R, PI3K, AKT, ERK, SHC, and combinations thereof in the cellular extract;
- (d) comparing the expression level and/or activation level of the one or more analytes determined in step (c) to a reference expression and/or activation profile of the one or more analytes that is generated in the absence of the anticancer drug to predict the likelihood that the subject will respond to treatment with the anticancer drug; and
- (e) indicating that the subject having the colorectal cancer will likely respond to treatment with the anticancer drug (e.g., the subject having the colorectal cancer has an increased likelihood or probability of response to treatment with the anticancer drug) when the expression level and/or activation level determined for the one or more analytes is changed (e.g., substantially decreased) compared to the reference expression and/or activation profile.
-
- (c′) genotyping for the presence or absence of a variant allele (e.g., somatic mutation) at a polymorphic site in an oncogene such as KRAS, BRAF, PIK3CA, and/or EGFR (e.g., one or more somatic mutations at one, two, three, four, five, or more polymorphic sites such as a single nucleotide polymorphism (SNP) in one or more of these genes) in a cellular extract produced from an isolated cancer cell (e.g., an aliquot of the cellular extract used in step (c)).
TABLE 1 | |||
EGFR (ErbB1) (A) | HER-2 (ErbB2) (C) | HER-3 (ErbB3) (E) | HER-4 (ErbB4) target |
Cetuximab | Trastuzumab | Antibody (U3) | |
Panitumumab | (HERCEPTIN ®) | ||
Matuzumab | Pertuzumab (2C4) | ||
Nimotuzumab | BMS-599626* | ||
ErbB1 vaccine | |||
*Heterodimerization HER-1/2; | |||
Phase 1 | |||
EGFR (ErbB1) (B) | HER-2 (ErbB2) (D) | ErbB1/2 (F) | ErbB1/2/4 (G) |
Erlotinib | CP-724714 (Pfizer) | Lapatinib (TYKERB ®) | Canertinib* |
Gefitinib | HKI-272* | ARRY-334543 | |
EKB 569* | HKI-357 (Preclinical) | JNJ-26483327 | |
CL-387-785** | BIBW 2992** | JNJ-26483327 | |
*(Wyeth, Irreversible, II | *Wyeth, Irreversible, I/II | *Pfizer, Irreversible, II | |
CRC) | NSCLC, Breast | NSCLC, Breast | |
**(Wyeth, Irreversible, | **Boehringer | ||
Preclinical) | Ingelheim, Irreversible, | ||
I/II Prostate, Ovarian, | |||
Breast | |||
Raf (H) | SRC (H) | Mek: (I) | NFkB-IkB (I) | ||
Sorafenib | AZ | PD-325901 (II: NSCLC) | |||
PLX4032 (Plexxikon) | AZD6244 - Array/Az | ||||
XL518 Exelisis/DNA | |||||
VEGFR2 and | |||
mTor (J) | PI3K (J) | VEGFR1 (K) | VEGFR1/2/3: |
Rad 001: Everolimus* | PX-866* | Avastin (DNA) | AZD 2171 (NSCLC, |
CRC) | |||
Temsirolimus** | HuMV833* | AMG-706 (+ PDGFR) | |
AP-23573*** | VEGF-Trap** | ||
*Everolimus (Novartis, | *P110alpha specific inhibition; | *(PDL) anti-VEGFa | |
combination with | ProIX Pharma; Preclinical | **Regeneron/Aventis | |
Gefetinib/Erlotinib; I/II: | NSCLC | (Receptor mimic) | |
NSCLC, Glioblastoma) | (Phase 2) | ||
**Temsirolimus (Wyeth, | |||
combination with | |||
Gefetinib/Erlotinib; I/II: | |||
NSCLC, Glioblastoma) | |||
***AP-23573 (Ariad, | |||
I/II: Endometrial) | |||
VEGFR2 target (L) | EPH A-D | |||
DC101* | CDP-791 (UCB) | Bay-579352 (+ PDGFR) | ||
IMC-IC11** | CP-547632* | ABT-869* | ||
IMC1121B Fully | AG13736** | BMS-540215 (+FGFR1) | ||
humanized | E-7080 (Eisai) | KRN-951 | ||
CDP-791*** | CHIR-258*** | BBIW | ||
Pazopanib**** | OSI-930 (+ cKit, PDGFR) | |||
*Imclone (Phase 2/3?) | *OSI, PFIZER: (+ ErbB1 + | *(+CSF1R, Erk, Flt-3, | ||
**Chimeric IgG1 against | PDGFR) (NSCLC, Ovarian | PDGFR) | ||
VEGFR2 | Phase 2) | |||
***Celltech, pegalated | **Pfizer: VEGFR1,2 and | |||
di-Fab antibody against | PDGFRbeta) (RCC II) | |||
R2 | ***(VEGFR1,2 | |||
****GSK, Multiple | FGFR3, PDGFR) | |||
myeloma, ovarian, RCC | ||||
Phase 3 enrollment | ||||
completed, sarcoma II) | ||||
VEGFR 2/ErbB1/2 | VEGFR2/1/3, Flt-3, | ||||
(ErbB1)/cMet/FGFR | VEGFR2/3/Raf/PDGFR/cKit/F | cFMS, PDGFR/cKit | |||
(M) | It-3 (N) | TIE 1/2 | (O) | ||
ZD6474* | Sorafenib* | PTK787 (Not cFMS, | |||
XL647** | FLT-3) | ||||
AEE 788*** | Sunitinib | ||||
XL-999 | |||||
SU-6668 (Pfizer) | |||||
GSK | |||||
AZ (AZD2171) | |||||
BMS | |||||
Novartis (AEE-788) | |||||
Amgen | |||||
Others | |||||
*(vandetanib) (Phase | *(RCC, HCC, NSCLC(III), | ||||
III: thyroid, NSCLC) | Melanoma(III)) | ||||
**(Exelixis; Also | |||||
EPHB2): (Patient | |||||
resistant to Erlotinib; | |||||
Asian patients) (Phase | |||||
2) | |||||
***(Novartis, Phase1/2) | |||||
PDGFR target (P) | Abl target: (Q) | FTL 3 | RET | ||
Tandutinib | Imatinib | ||||
Nilotinib | Dasatinib | ||||
Nilotinib | |||||
AT-9283 | |||||
AZD-0530 | |||||
Bosutinib | |||||
Kit target (R) | HGFR1/2 | FGFR1-4 | IGF-1R Target (S) | ||
AMG-706 | Chiron | Merck | |||
XL-880 | Pfizer | ||||
XL-999 | Novartis | ||||
HSP90 inhibitors: | Anti-Mitotic Drugs: | Other targets: | ||
IPI-504* | Docetaxel* | HDAC inhibitors | ||
17-AAG** | Paclitaxel** | BCL2 | ||
Vinblastine, Vincristine, | Chemotherapeutics | |||
Vinorelbine*** | (breakdown) | |||
Proteosome inhibitors | ||||
*(Infinity Pharma, | *(Microtubule stabilizer; | |||
Mutant ErbB1, I/II | Adjuvant and advanced | |||
multiple myeloma, | Breast cancer; NSCLC, | |||
GIST) | Androgen independent | |||
**(Kosan, I/II solid | Prostate cancer) | |||
tumors) | **(Microtubule stabilizer; | |||
Adjuvant and advanced | ||||
Breast cancer; NSCLC, | ||||
Ovarian cancer, AIDS related | ||||
Kaposi sarcoma) | ||||
***(Microtubule De-stabilizers) | ||||
TABLE 2 | ||||||||
Pathway 1 | ErbB1 | ErbB1 | ErbB1 | ErbB1 | ErbB1-PI3K | PTEN | ||
Phospho | Shc | ubiquitin | ||||||
Pathway 2 | ErbB1 | ErbB1VIII | ErbB1VIII | ErbB1VIII | ErbB1VIII | ErbB1VIII | PTEN | |
Phospho | Shc | ubiquitin | PI3K | |||||
Pathway 3 | ErbB2 | ErbB2 Phospho | HER-2 Shc | ErbB2:PI3K | ErbB2 | PTEN | ||
Complex | ubiquitin | |||||||
Pathway 4 | ErbB2 | P95Truncated | ErbB2Phospho | P95Truncated | HER-2 Shc | ERBB2:PI3K | ErbB2 | P95ErbB2:PI3K |
ErbB2 | ERBB2 | Complex | ubiquitin | |||||
Phospho | ||||||||
Pathway 5 | ErbB3 | ErbB3 Phospho | ErbB3:PI3K | ErbB3 PI3K | ErbB3:Shc | |||
Complex | Phospho | |||||||
Pathway 6 | ErbB4 | ErbB4 Phospho | ErbB4:Shc | |||||
Pathway 7 | IGF-1R | IGF-1RPhospho | IGF-1R:IRS | IRS:PI3K | Phospho IRS | IGF-1R:PI3K | ||
Pathway 8 | INSR | INSRPhospho | ||||||
Pathway 9 | KIT | KIT Phospho | ||||||
Pathway 10 | FLT3 | FLT3Phospho | ||||||
Pathway 11 | HGFR 1 | HGFR 1 | ||||||
Phospho | ||||||||
Pathway 12 | HGFR 2 | HGFR 2 | ||||||
Phospho | ||||||||
Pathway 13 | RET | RET Phospho | ||||||
Pathway 14 | PDGFR | PDGFR alpha | ||||||
alpha | Phospho | |||||||
Pathway 15 | PDGFR | PDGFR beta | ||||||
beta | Phospho | |||||||
Pathway 16 | VEGFR 1 | VEGFR 1 | VEGFR 1: | VEGFR 1: | ||||
Phospho | PLCγComplex | Src | ||||||
Pathway 17 | VEGFR 2 | VEGFR 2 | VEGFR 2: | VEGFR 2: | VEGFR-2/ | VEGFR-2, | ||
Phospho | PLCγ | Src | heparin | VE-cadherin | ||||
complex | sulphate | complex | ||||||
complex | ||||||||
Pathway 18 | VEGFR 3 | VEGFR 3 | ||||||
Phospho | ||||||||
Pathway 19 | FGFR 1 | FGFR 1 | ||||||
Phospho | ||||||||
Pathway 20 | FGFR 2 | FGFR 2 | ||||||
Phospho | ||||||||
Pathway 21 | FGFR 3 | FGFR 3 | ||||||
Phospho | ||||||||
Pathway 22 | FGFR 4 | FGFR 4 | ||||||
Phospho | ||||||||
Pathway 23 | TIE 1 | TIE 1 Phospho | ||||||
Pathway 24 | TIE 2 | TIE 2 Phospho | ||||||
Pathway 25 | EPHA | EPHA Phospho | ||||||
Pathway 26 | EPHB | EPHB Phospho | ||||||
Pathway 27 | NFkB-IkB | phospho-IκB | Total NFκB | Total P65 | ||||
complex | (S32) | Phospho | IkBa | |||||
Total IkB | NFκB(S536) | Phospho | ||||||
P65 IkBa | ||||||||
Pathway 28 | ER | Phospho ER | ER-AIB1 | Other ER | ||||
complexes | ||||||||
Pathway 29 | PR | Phospho Pr | PR | |||||
complexes | ||||||||
Pathway 30 | Hedgehog | |||||||
Pathway | ||||||||
Pathway 31 | Wnt | |||||||
pathway | ||||||||
Pathway 32 | Notch | |||||||
Pathway | ||||||||
Pathway 33 | Total Mek | Total Erk | Total Rsk-1 | Total Stat3 | Phospho | Total Fak | Total cSrc | Total Ras |
Phospho | Phospho Erk | Phospho Rsk-1 | Phospho Stat-3 | Bad (S112) | Phospho | Phospho | Phospho | |
Mek | (T202/Y204) | (T357/S363) | (Y705) | Bad (total) | Fak | cSrc(Y416) | Ras | |
(S217/S221) | (S727) | (Y576) | ||||||
Total Stat 1 | ||||||||
Phospho | ||||||||
Stat1 (Y 701) | ||||||||
Pathway 34 | Akt | Phospho Akt | Phospho Bad | Phospho Bad | Bad: 14-3-3 | Total | Total | GSK3beta |
(Total) | (T308) | (S112) | (S136) | complex | mTor | p70S6K | Total | |
Phospho | Bad (total) | Phospho | Phospho | (Phospho | ||||
Akt | mTor | p70S6K | Ser9) | |||||
(T473) | (S2448) | (T229) | ||||||
(T389) | ||||||||
Pathway 35 | Total Jnk | Total P38 | Total Rb | Total p53 | phospho- | Total | Total | |
Phospho | Phospho P38 | Phospho Rb | Phospho p53 | CREB(S133) | c-Jun | Paxillin | ||
Jnk | (T180/Y182) | (S249/T252) | (S392) | Total | phospho- | Phospho | ||
(T183/Y185) | Phospho Rb | Phospho p53 | CREB | c-Jun; | Paxillin | |||
(S780) | (S20) | (S63) | (Y118) | |||||
Pathway 36 | Ki67 | Cleaved | TOPO2 | |||||
Caspase 3,8,9 | ||||||||
others | ||||||||
Pathway 37 | TGFbeta | |||||||
-
- (a) detecting the expression level and/or activation level of one or more non-ErbB RTKs in a cancer cell obtained from the subject; and
- (b) determining that an anticancer drug targeting one or more non-ErbB RTKs should be administered to the subject when a higher expression level or activation level of one or more non-ErbB RTKs is detected compared to the expression level or activation level of the same non-ErbB RTKs in a cancer cell from a KRAS wild-type subject.
-
- (i) incubating (e.g., contacting) a cellular extract produced from the cell with one or a plurality of dilution series of capture antibodies (e.g., capture antibodies specific for one or more analytes) to form a plurality of captured analytes, wherein the capture antibodies are restrained on a solid support (e.g., to transform the analytes present in the cellular extract into complexes of captured analytes comprising the analytes and capture antibodies);
- (ii) incubating (e.g., contacting) the plurality of captured analytes with detection antibodies comprising one or a plurality of first and second activation state-independent antibodies specific for the corresponding analytes (e.g., first and second activation state-independent antibodies specific for the one or more analytes) to form a plurality of detectable captured analytes (e.g., to transform the complexes of captured analytes into complexes of detectable captured analytes comprising the captured analytes and detection antibodies),
- wherein the first activation state-independent antibodies are labeled with a facilitating moiety, the second activation state-independent antibodies are labeled with a first member of a signal amplification pair, and the facilitating moiety generates an oxidizing agent which channels to and reacts with the first member of the signal amplification pair;
- (iii) incubating (e.g., contacting) the plurality of detectable captured analytes with a second member of the signal amplification pair to generate an amplified signal; and
- (iv) detecting the amplified signal generated from the first and second members of the signal amplification pair.
-
- (i) incubating (e.g., contacting) a cellular extract produced from the cell with a plurality of beads specific for an extracellular domain (ECD) binding region of a full-length receptor (e.g., full-length HER2);
- (ii) removing the plurality of beads from the cellular extract, thereby removing the full-length receptor (e.g., full-length HER2)to form a cellular extract devoid of the full-length receptor (e.g., full-length HER2) (e.g., to transform the cellular extract into a cellular extract devoid of a specific full-length receptor or family of full-length receptors);
- (iii) incubating (e.g., contacting) the cellular extract devoid of the full-length receptor (e.g., full-length HER2) with one or a plurality of capture antibodies specific for an intracellular domain (ICD) binding region of the full-length receptor (e.g., full-length HER2) to form a plurality of captured truncated receptors, wherein the capture antibodies are restrained on a solid support (e.g., to transform the truncated receptors present in a full-length receptor-depleted cellular extract into complexes of truncated receptors and capture antibodies);
- (iv) incubating the plurality of captured truncated receptors with detection antibodies comprising one or a plurality of first and second activation state-independent antibodies specific for an ICD binding region of the full-length receptor (e.g., full-length HER2) to form a plurality of detectable captured truncated receptors (e.g., to transform the complexes of captured truncated receptors into complexes of detectable captured truncated receptors comprising the captured truncated receptors and detection antibodies),
- wherein the first activation state-independent antibodies are labeled with a facilitating moiety, the second activation state-independent antibodies are labeled with a first member of a signal amplification pair, and the facilitating moiety generates an oxidizing agent which channels to and reacts with the first member of the signal amplification pair;
- (v) incubating (e.g., contacting) the plurality of detectable captured truncated receptors with a second member of the signal amplification pair to generate an amplified signal; and
- (vi) detecting the amplified signal generated from the first and second members of the signal amplification pair.
-
- (i) incubating (e.g., contacting) a cellular extract produced from the cell with a dilution series of capture antibodies (e.g., capture antibodies specific for one or more analytes) to form a plurality of captured analytes, wherein the capture antibodies are restrained on a solid support (e.g., to transform the analytes present in the cellular extract into complexes of captured analytes comprising the analytes and capture antibodies);
- (ii) incubating (e.g., contacting) the plurality of captured analytes with detection antibodies comprising activation state-independent antibodies specific for the corresponding analytes (e.g., activation state-independent antibodies specific for the one or more analytes) and activation state-dependent antibodies specific for the corresponding analytes (e.g., activation state-dependent antibodies specific for the one or more analytes) to form a plurality of detectable captured analytes (e.g., to transform the complexes of captured analytes into complexes of detectable captured analytes comprising the captured analytes and detection antibodies),
- wherein the activation state-independent antibodies are labeled with a facilitating moiety, the activation state-dependent antibodies are labeled with a first member of a signal amplification pair, and the facilitating moiety generates an oxidizing agent which channels to and reacts with the first member of the signal amplification pair;
- (iii) incubating (e.g., contacting) the plurality of detectable captured analytes with a second member of the signal amplification pair to generate an amplified signal; and
- (iv) detecting the amplified signal generated from the first and second members of the signal amplification pair.
-
- (i) incubating (e.g., contacting) a cellular extract produced from the cell with a plurality of beads specific for an extracellular domain (ECD) binding region of a full-length receptor (e.g., full-length HER2);
- (ii) removing the plurality of beads from the cellular extract, thereby removing the full-length receptor (e.g., full-length HER2) to form a cellular extract devoid of the full-length receptor (e.g., full-length HER2) (e.g., to transform the cellular extract into a cellular extract devoid of a specific full-length receptor or family of full-length receptors);
- (iii) incubating (e.g., contacting) the cellular extract devoid of the full-length receptor (e.g., full-length HER2) with a plurality of capture antibodies specific for an intracellular domain (ICD) binding region of the full-length receptor (e.g., full-length HER2) to form a plurality of captured truncated receptors, wherein the capture antibodies are restrained on a solid support (e.g., to transform the truncated receptors present in a full-length receptor-depleted cellular extract into complexes of truncated receptors and capture antibodies);
- (iv) incubating (e.g., contacting) the plurality of captured truncated receptors with detection antibodies comprising activation state-independent antibodies and activation state-dependent antibodies specific for an ICD binding region of the full-length receptor (e.g., full-length HER2) to form a plurality of detectable captured truncated receptors (e.g., to transform the complexes of captured truncated receptors into complexes of detectable captured truncated receptors comprising the captured truncated receptors and detection antibodies),
- wherein the activation state-independent antibodies are labeled with a facilitating moiety, the activation state-dependent antibodies are labeled with a first member of a signal amplification pair, and the facilitating moiety generates an oxidizing agent which channels to and reacts with the first member of the signal amplification pair;
- (v) incubating (e.g., contacting) the plurality of detectable captured truncated receptors with a second member of the signal amplification pair to generate an amplified signal; and
- (vi) detecting the amplified signal generated from the first and second members of the signal amplification pair.
-
- (i) incubating the cellular extract with one or a plurality of dilution series of capture antibodies to form a plurality of captured analytes;
- (ii) incubating the plurality of captured analytes with detection antibodies specific for the corresponding analytes to form a plurality of detectable captured analytes, wherein the detection antibodies comprise activation state-dependent antibodies for detecting the activation (e.g., phosphorylation) level of the analyte or activation state-independent antibodies for detecting the expression level (e.g., total amount) of the analyte;
- (iii) incubating the plurality of detectable captured analytes with first and second members of a signal amplification pair to generate an amplified signal; and
- (iv) detecting the amplified signal generated from the first and second members of the signal amplification pair.
-
- (i) incubating the cellular extract with a plurality of beads specific for an extracellular domain (ECD) binding region of a full-length receptor;
- (ii) removing the plurality of beads from the cellular extract, thereby removing the full-length receptor to form a cellular extract devoid of the full-length receptor;
- (iii) incubating the cellular extract devoid of the full-length receptor with a dilution series of one or a plurality of capture antibodies specific for an intracellular domain (ICD) binding region of the full-length receptor to form a plurality of captured truncated receptors;
- (iv) incubating the plurality of captured truncated receptors with detection antibodies specific for an ICD binding region of the full-length receptor to form a plurality of detectable captured truncated receptors, wherein the detection antibodies comprise activation state-dependent antibodies for detecting the activation (e.g., phosphorylation) level of the truncated receptor or activation state-independent antibodies for detecting the expression level (e.g., total amount) of the truncated receptor;
- (v) incubating the plurality of detectable captured truncated receptors with first and second members of a signal amplification pair to generate an amplified signal; and
- (vi) detecting an amplified signal generated from the first and second members of the signal amplification pair.
-
- (i) incubating the cellular extract with one or a plurality of dilution series of capture antibodies to form a plurality of captured analytes;
- (ii) incubating the plurality of captured analytes with detection antibodies comprising one or a plurality of activation state-independent antibodies and one or a plurality of activation state-dependent antibodies specific for the corresponding analytes to form a plurality of detectable captured analytes,
- wherein the activation state-independent antibodies are labeled with a facilitating moiety, the activation state-dependent antibodies are labeled with a first member of a signal amplification pair, and the facilitating moiety generates an oxidizing agent which channels to and reacts with the first member of the signal amplification pair;
- (iii) incubating the plurality of detectable captured analytes with a second member of the signal amplification pair to generate an amplified signal; and
- (iv) detecting the amplified signal generated from the first and second members of the signal amplification pair.
-
- (i) incubating the cellular extract with a plurality of beads specific for an extracellular domain (ECD) binding region of a full-length receptor;
- (ii) removing the plurality of beads from the cellular extract, thereby removing the full-length receptor to form a cellular extract devoid of the full-length receptor;
- (iii) incubating the cellular extract devoid of the full-length receptor with one or a plurality of capture antibodies specific for an intracellular domain (ICD) binding region of the full-length receptor to form a plurality of captured truncated receptors;
- (iv) incubating the plurality of captured truncated receptors with detection antibodies comprising one or a plurality of activation state-independent antibodies and one or a plurality of activation state-dependent antibodies specific for an ICD binding region of the full-length receptor to form a plurality of detectable captured truncated receptors,
- wherein the activation state-independent antibodies are labeled with a facilitating moiety, the activation state-dependent antibodies are labeled with a first member of a signal amplification pair, and the facilitating moiety generates an oxidizing agent which channels to and reacts with the first member of the signal amplification pair;
- (v) incubating the plurality of detectable captured truncated receptors with a second member of the signal amplification pair to generate an amplified signal; and
- (vi) detecting the amplified signal generated from the first and second members of the signal amplification pair.
-
- (i) incubating the cellular extract with one or a plurality of dilution series of capture antibodies to form a plurality of captured analytes;
- (ii) incubating the plurality of captured analytes with detection antibodies comprising one or a plurality of first and second activation state-independent antibodies specific for the corresponding analytes to form a plurality of detectable captured analytes,
- wherein the first activation state-independent antibodies are labeled with a facilitating moiety, the second activation state-independent antibodies are labeled with a first member of a signal amplification pair, and the facilitating moiety generates an oxidizing agent which channels to and reacts with the first member of the signal amplification pair;
- (iii) incubating the plurality of detectable captured analytes with a second member of the signal amplification pair to generate an amplified signal; and
- (iv) detecting the amplified signal generated from the first and second members of the signal amplification pair.
-
- (i) incubating the cellular extract with a plurality of beads specific for an extracellular domain (ECD) binding region of a full-length receptor;
- (ii) removing the plurality of beads from the cellular extract, thereby removing the full-length receptor to form a cellular extract devoid of the full-length receptor;
- (iii) incubating the cellular extract devoid of the full-length receptor with one or a plurality of capture antibodies specific for an intracellular domain (ICD) binding region of the full-length receptor to form a plurality of captured truncated receptors;
- (iv) incubating the plurality of captured truncated receptors with detection antibodies comprising one or a plurality of first and second activation state-independent antibodies specific for an ICD binding region of the full-length receptor to form a plurality of detectable captured truncated receptors,
- wherein the first activation state-independent antibodies are labeled with a facilitating moiety, the second activation state-independent antibodies are labeled with a first member of a signal amplification pair, and the facilitating moiety generates an oxidizing agent which channels to and reacts with the first member of the signal amplification pair;
- (v) incubating the plurality of detectable captured truncated receptors with a second member of the signal amplification pair to generate an amplified signal; and
- (vi) detecting the amplified signal generated from the first and second members of the signal amplification pair.
Claims (10)
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US9719995B2 (en) * | 2011-02-03 | 2017-08-01 | Pierian Holdings, Inc. | Drug selection for colorectal cancer therapy using receptor tyrosine kinase profiling |
KR101851425B1 (en) | 2011-09-02 | 2018-04-23 | 네스텍 소시에테아노님 | Profiling of signal pathway proteins to determine therapeutic efficacy |
WO2015105996A2 (en) * | 2014-01-09 | 2015-07-16 | Sloan-Kettering Institute For Cancer Research | Treatment of tumors expressing mutant p53 |
US20210318318A1 (en) * | 2018-08-31 | 2021-10-14 | Institute For Cancer Research D/B/A The Research Institute Of Fox Chase Cancer Center | Kinase Activity In Tumors |
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